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Buonfiglio F, Böhm EW, Tang Q, Daiber A, Gericke A. Revisiting the renin-angiotensin-aldosterone system in the eye: Mechanistic insights and pharmacological targets. Pharmacol Res 2025; 216:107771. [PMID: 40348100 DOI: 10.1016/j.phrs.2025.107771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 04/22/2025] [Accepted: 05/07/2025] [Indexed: 05/14/2025]
Abstract
The renin-angiotensin-aldosterone system (RAAS) plays a fundamental role in regulating blood pressure and fluid homeostasis through key effectors such as angiotensin II and aldosterone. These agents and their receptors have become crucial molecular targets in several cardiovascular and renal diseases. Over the past few decades, a growing body of evidence has revealed the presence of RAAS components in ocular structures, suggesting a tissue-specific RAAS within the eye. Building on this knowledge, studies have indicated that the ocular RAAS plays a significant role in the pathogenesis of various eye diseases. An impaired and overactivated RAAS contributes to the development of severe and widespread disorders affecting both the anterior and posterior segments of the eye. In this context, the current work aims to delve into the pivotal molecular pathways involving the RAAS, with an in-depth exploration of the ocular pathophysiology. It focuses on the relationship between overactivation of the RAAS and oxidative stress, as well as the exacerbation of neovascularization and inflammatory processes. The objective is to provide an updated and comprehensive understanding of the role of the RAAS in ophthalmological diseases, highlighting the therapeutic potential of RAAS modulators and discussing the controversies and challenges in this area of research.
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Affiliation(s)
- Francesco Buonfiglio
- Department of Ophthalmology, University Medical Center of the Johannes Gutenberg, University, Langenbeckstr.1, Mainz 55131, Germany.
| | - Elsa Wilma Böhm
- Department of Ophthalmology, University Medical Center of the Johannes Gutenberg, University, Langenbeckstr.1, Mainz 55131, Germany.
| | - Qi Tang
- Department of Ophthalmology, University Medical Center of the Johannes Gutenberg, University, Langenbeckstr.1, Mainz 55131, Germany.
| | - Andreas Daiber
- Department of Cardiology I, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz 55131, Germany.
| | - Adrian Gericke
- Department of Ophthalmology, University Medical Center of the Johannes Gutenberg, University, Langenbeckstr.1, Mainz 55131, Germany.
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2
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Souza‐Silva IM, Carregari VC, Steckelings UM, Verano‐Braga T. Phosphoproteomics for studying signaling pathways evoked by hormones of the renin-angiotensin system: A source of untapped potential. Acta Physiol (Oxf) 2025; 241:e14280. [PMID: 39821680 PMCID: PMC11737475 DOI: 10.1111/apha.14280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 12/20/2024] [Accepted: 12/31/2024] [Indexed: 01/19/2025]
Abstract
The Renin-Angiotensin System (RAS) is a complex neuroendocrine system consisting of a single precursor protein, angiotensinogen (AGT), which is processed into various peptide hormones, including the angiotensins [Ang I, Ang II, Ang III, Ang IV, Ang-(1-9), Ang-(1-7), Ang-(1-5), etc] and Alamandine-related peptides [Ang A, Alamandine, Ala-(1-5)], through intricate enzymatic pathways. Functionally, the RAS is divided into two axes with opposing effects: the classical axis, primarily consisting of Ang II acting through the AT1 receptor (AT1R), and in contrast the protective axis, which includes the receptors Mas, AT2R and MrgD and their respective ligands. A key area of RAS research is to gain a better understanding how signaling cascades elicited by these receptors lead to either "classical" or "protective" effects, as imbalances between the two axes can contribute to disease. On the other hand, therapeutic benefits can be achieved by selectively activating protective receptors and their associated signaling pathways. Traditionally, robust "hypothesis-driven" methods like Western blotting have built a solid knowledge foundation on RAS signaling. In this review, we introduce untargeted mass spectrometry-based phosphoproteomics, a "hypothesis-generating approach", to explore RAS signaling pathways. This technology enables the unbiased discovery of phosphorylation events, offering insights into previously unknown signaling mechanisms. We review the existing studies which used phosphoproteomics to study RAS signaling and discuss potential future applications of phosphoproteomics in RAS research including advantages and limitations. Ultimately, phosphoproteomics represents a so far underused tool for deepening our understanding of RAS signaling and unveiling novel therapeutic targets.
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Affiliation(s)
- Igor Maciel Souza‐Silva
- Max‐Delbrück‐Center for Molecular Medicine in the Helmholtz AssociationBerlinGermany
- Department of Molecular Medicine, Cardiovascular and Renal Research UnitUniversity of Southern DenmarkOdense MDenmark
| | - Victor Corasolla Carregari
- Laboratório de Neuroproteômica, Instituto de BiologiaUniversidade de CampinasSão PauloBrazil
- Department of Biochemistry and Molecular Biology, Protein Research GroupUniversity of Southern DenmarkOdense MDenmark
| | - U. Muscha Steckelings
- Department of Molecular Medicine, Cardiovascular and Renal Research UnitUniversity of Southern DenmarkOdense MDenmark
| | - Thiago Verano‐Braga
- Department of Molecular Medicine, Cardiovascular and Renal Research UnitUniversity of Southern DenmarkOdense MDenmark
- Departamento de Fisiologia e BiofísicaUniversidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
- Instituto Nacional de Ciência e Tecnologia Em Nanobiofarmacêutica (INCT‐Nanobiofar)Universidade Federal de Minas GeraisBelo HorizonteMinas GeraisBrazil
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3
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Bansal N, Kathuria D, Babu AM, Dhiman S, Lakhanpal S, Prasad KN, Kumar R, Tyagi Y, Kumar B, Singh MP, Gaidhane AM. A perspective on small molecules targeting the renin-angiotensin-aldosterone system and their utility in cardiovascular diseases: exploring the structural insights for rational drug discovery and development. RSC Med Chem 2025:d4md00720d. [PMID: 39925732 PMCID: PMC11803303 DOI: 10.1039/d4md00720d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 01/12/2025] [Indexed: 02/11/2025] Open
Abstract
Renin-angiotensin-aldosterone system (RAAS) is crucial in cardiovascular homeostasis. Any disruption in this homeostasis often leads to numerous cardiovascular diseases (CVDs) and non-cardiovascular diseases. Small molecules that show ability toward mechanically modulating RAAS components have been developed to address this problem, thus providing opportunities for innovative drug discovery and development. This review is put forth to provide a comprehensive understanding not only on the signaling mechanisms of RAAS that lead to cardiovascular events but also on the use of small molecules targeting the modulation of RAAS components. Further, the detailed descriptions of the drugs affecting the RAAS and their pharmacodynamics, kinetics, and metabolism profiles are provided. This article also covers the limitations of the present therapeutic armory, followed by their mechanistic insights. A brief discussion is offered on the analysis of the chemical space parameters of the drugs affecting RAAS compared to other cardiovascular and renal categories of medications approved by the US FDA. This review provides structural insights and emphasizes the importance of integrating the current therapeutic regimen with pharmacological tactics to accelerate the development of new therapeutics targeting the RAAS components for improved and efficacious cardiovascular outcomes. Finally, chemical spacing parameters of RAAS modulators are provided, which will help in understanding their peculiarities in modulating the RAAS signaling through structural and functional analyses. Furthermore, this review will assist medicinal chemists working in this field in developing better drug regimens with improved selectivity and efficacy.
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Affiliation(s)
- Nisha Bansal
- Gramothan Vidyapeeth Home Science Girls PG College Sangaria Rajasthan India
| | - Deepika Kathuria
- University Centre for Research and Development, Chandigarh University Gharuan 140413 Punjab India
| | - Arockia M Babu
- Institute of Pharmaceutical Research, GLA University 17, Km Stone, National Highway #2, Delhi-Mathura Road Mathura India
| | - Sonia Dhiman
- Centre of Research Impact and Outcome, Chitkara University Rajpura-140417 Punjab India
| | - Sorabh Lakhanpal
- Division of Research and Development, Lovely Professional University Phagwara 144411 Punjab India
| | - K Nagendra Prasad
- KKR and KSR Institute of Technology and Sciences Guntur 522017 Andhra Pradesh India
| | - Roshan Kumar
- Graphic Era (Deemed to be University) Clement Town Dehradun-248002 India
| | - Yogita Tyagi
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University Prem Nagar Dehradun 248007 Uttarakhand India
| | - Bhupinder Kumar
- Department of Pharmaceutical Sciences, HNB Garhwal University, Chauras Campus Srinagar, Garhwal-246174 Uttarakhand India
| | - Mahendra Pratap Singh
- Center for Global Health Research, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences, Saveetha University Chennai India
| | - Abhay M Gaidhane
- Jawaharlal Nehru Medical College, and Global Health Academy, School of Epidemiology and Public Health, Datta Meghe Institute of Higher Education Wardha India
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4
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Xie P, Guo L, Yu Q, Zhao Y, Yu M, Wang H, Wu M, Xu W, Xu M, Zhu XD, Xu Y, Xiao YS, Huang C, Zhou J, Fan J, Hung MC, Sun H, Ye QH, Zhang B, Li H. ACE2 Enhances Sensitivity to PD-L1 Blockade by Inhibiting Macrophage-Induced Immunosuppression and Angiogenesis. Cancer Res 2025; 85:299-313. [PMID: 39495239 DOI: 10.1158/0008-5472.can-24-0954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Revised: 08/07/2024] [Accepted: 10/24/2024] [Indexed: 11/05/2024]
Abstract
Anti-PD-L1-based combination immunotherapy has become the first-line treatment for unresectable hepatocellular carcinoma (HCC). However, the objective response rate is lower than 40%, highlighting the need to identify mechanisms of tolerance to immune checkpoint inhibitors and accurate biomarkers of response. In this study, we used next-generation sequencing to analyze HCC samples from 10 patients receiving anti-PD-L1 therapy. Activation of the renin-angiotensin system was elevated in nonresponders compared with responders, and angiotensin-converting enzyme 2 (ACE2) expression was significantly downregulated in nonresponders. ACE2 deficiency promoted HCC development and anti-PD-L1 resistance, whereas ACE2 overexpression inhibited HCC progression in immune-competent mice. Mass cytometry by time of flight revealed that ACE2-deficient murine orthotopic tumor tissues featured elevated M2-like tumor-associated macrophages, displayed a CCR5+PD-L1+ immunosuppressive phenotype, and exhibited high VEGFα expression. ACE2 downregulated tumor-intrinsic chemokine (C-C motif) ligand 5 expression by suppressing NF-κB signaling through the ACE2/angiotensin-(1-7)/Mas receptor axis. The lower chemokine (C-C motif) ligand 5 levels led to reduced activation of the JAK-STAT3 pathway and suppressed PD-L1 and VEGFα expression in macrophages, blocking macrophage infiltration and M2-like polarization. Pharmacologic targeting of CCR5 using maraviroc enhanced the tumor-suppressive effect of anti-PD-L1 therapy. Together, these findings suggest that activation of the ACE2 axis overcomes the immunosuppressive microenvironment of HCC and may serve as an immunotherapeutic target and predictive biomarker of response to PD-L1 blockade. Significance: ACE2 regulates the immune landscape of hepatocellular carcinoma by abrogating M2-like macrophage polarization and sensitizes tumors to anti-PD-L1, suggesting that harnessing the ACE2 axis could be a promising strategy to improve immunotherapy efficacy.
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Affiliation(s)
- Peiyi Xie
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China
| | - Lei Guo
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China
| | - Qiang Yu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China
| | - Yufei Zhao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China
| | - Mincheng Yu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China
| | - Hui Wang
- Department of Molecular Biology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Mengyuan Wu
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China
| | - Wenxin Xu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China
| | - Min Xu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China
| | - Xiao-Dong Zhu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China
| | - Yongfeng Xu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China
| | - Yong-Sheng Xiao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China
| | - Cheng Huang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China
| | - Mien-Chie Hung
- Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology, and Center for Molecular Medicine, China Medical University, Taichung, Taiwan
| | - Huichuan Sun
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China
| | - Qing-Hai Ye
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China
| | - Bo Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China
| | - Hui Li
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P.R. China
- Shanghai Medical College and Zhongshan Hospital Immunotherapy Technology Translational Research Center, Shanghai, P.R. China
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5
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Dominici FP, Gironacci MM, Narvaez Pardo JA. Therapeutic opportunities in targeting the protective arm of the renin-angiotensin system to improve insulin sensitivity: a mechanistic review. Hypertens Res 2024; 47:3397-3408. [PMID: 39363004 DOI: 10.1038/s41440-024-01909-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 08/04/2024] [Accepted: 09/02/2024] [Indexed: 10/05/2024]
Abstract
In recent years, the knowledge of the physiological and pathophysiological roles of the renin-angiotensin system (RAS) in glucose metabolism has advanced significantly. It is now well-established that blockade of the angiotensin AT1 receptor (AT1R) improves insulin sensitivity. Activation of the AT2 receptor (AT2R) and the MAS receptor are significant contributors to this beneficial effect. Elevated availability of angiotensin (Ang) II) for interaction with the AT2R and increased Ang-(1-7) formation during AT1R blockade mediate these effects. The ongoing development of selective AT2R agonists, such as compound 21 and the novel Ang III peptidomimetics, has significantly advanced the exploration of the role of AT2R in metabolism and its potential as a therapeutic target. These agents show promise, particularly when RAS inhibition is contraindicated. Additionally, other RAS peptides, including Ang IV, des-Asp-Ang I, Ang-(1-9), and alamandine, hold therapeutic capability for addressing metabolic disturbances linked to type 2 diabetes. The possibility of AT2R heteromerization with either AT1R or MAS receptor offers an exciting area for future research, particularly concerning therapeutic strategies to improve glycemic control. This review focuses on therapeutic opportunities to improve insulin sensitivity, taking advantage of the protective arm of the RAS.
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Affiliation(s)
- Fernando P Dominici
- Departamento de Química Biológica and IQUIFIB (UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
| | - Mariela M Gironacci
- Departamento de Química Biológica and IQUIFIB (UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Jorge A Narvaez Pardo
- Departamento de Química Biológica and IQUIFIB (UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
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6
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Rukavina Mikusic NL, Silva MG, Erra Díaz FA, Pineda AM, Ferragut F, Gómez KA, Mazzitelli L, Gonzalez Maglio DH, Nuñez M, Santos RAS, Grecco HE, Gironacci MM. Alamandine, a protective component of the renin-angiotensin system, reduces cellular proliferation and interleukin-6 secretion in human macrophages through MasR-MrgDR heteromerization. Biochem Pharmacol 2024; 229:116480. [PMID: 39128587 DOI: 10.1016/j.bcp.2024.116480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 07/21/2024] [Accepted: 08/08/2024] [Indexed: 08/13/2024]
Abstract
Alamandine (ALA) exerts protective effects similar to angiotensin (Ang) (1-7) through Mas-related G protein-coupled receptor type D receptor (MrgDR) activation, distinct from Mas receptor (MasR). ALA induces anti-inflammatory effects in mice but its impact in human macrophages remains unclear. We aimed to investigate the anti-inflammatory effects of ALA in human macrophages. Interleukin (IL)-6 and IL-1β were measured by ELISA in human THP-1 macrophages and human monocyte-derived macrophages exposed to lipopolysaccharide (LPS). Consequences of MasR-MrgDR heteromerization were investigated in transfected HEK293T cells. ALA decreased IL-6 and IL-1β secretion in LPS-activated THP-1 macrophages. The ALA-induced decrease in IL-6 but not in IL-1β was prevented by MasR blockade and MasR downregulation, suggesting MasR-MrgDR interaction. In human monocyte-derived M1 macrophages, ALA decreased IL-1β secretion independently of MasR. MasR-MrgDR interaction was confirmed in THP-1 macrophages, human monocyte-derived macrophages, and transfected HEK293T cells. MasR and MrgDR formed a constitutive heteromer that was not influenced by ALA. ALA promoted Akt and ERK1/2 activation only in cells expressing MasR-MrgDR heteromers, and this effect was prevented by MasR blockade. While Ang-(1-7) reduced cellular proliferation in MasR -but not MrgDR- expressing cells, ALA antiproliferative effect was elicited in cells expressing MasR-MrgDR heteromers. ALA also induced an antiproliferative response in THP-1 cells and this effect was abolished by MasR blockade, reinforcing MasR-MrgDR interaction. MasR-MrgDR heteromerization is crucial for ALA-induced anti-inflammatory and antiproliferative responses in human macrophages. This study broaden our knowledge of the protective axis of the RAS, thus enabling novel therapeutic approaches in inflammatory-associated diseases.
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Affiliation(s)
- Natalia L Rukavina Mikusic
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, IQUIFIB (UBA-CONICET), Buenos Aires, Argentina
| | - Mauro G Silva
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, IQUIFIB (UBA-CONICET), Buenos Aires, Argentina
| | | | - Angélica M Pineda
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, IQUIFIB (UBA-CONICET), Buenos Aires, Argentina
| | - Fátima Ferragut
- Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (CONICET), Buenos Aires, Argentina
| | - Karina A Gómez
- Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (CONICET), Buenos Aires, Argentina
| | - Luciana Mazzitelli
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, IQUIFIB (UBA-CONICET), Buenos Aires, Argentina
| | - Daniel H Gonzalez Maglio
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Inmunología-IDEHU, Buenos Aires, Argentina
| | - Myriam Nuñez
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Matemáticas, Dpto de Físico-Matemáticas, Buenos Aires, Argentina
| | - Robson A S Santos
- Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Hernán E Grecco
- Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Dpto. de Física, Buenos Aires, Argentina
| | - Mariela M Gironacci
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, IQUIFIB (UBA-CONICET), Buenos Aires, Argentina.
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7
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Buonfiglio F, Pfeiffer N, Gericke A. Glaucoma and the ocular renin-angiotensin-aldosterone system: Update on molecular signalling and treatment perspectives. Cell Signal 2024; 122:111343. [PMID: 39127136 DOI: 10.1016/j.cellsig.2024.111343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 07/29/2024] [Accepted: 08/08/2024] [Indexed: 08/12/2024]
Abstract
Glaucoma, a leading cause of blindness worldwide, encompasses a group of pathological conditions affecting the optic nerve and is characterized by progressive retinal ganglion cell loss, cupping of the optic nerve head, and distinct visual field defects. While elevated intraocular pressure (IOP) is the main risk factor for glaucoma, many patients do not have elevated IOP. Consequently, other risk factors, such as ocular blood flow abnormalities and immunological factors, have been implicated in its pathophysiology. Traditional therapeutic strategies primarily aim to reduce IOP, but there is growing interest in developing novel treatment approaches to improve disease management and reduce the high rates of severe visual impairment. In this context, targeting the ocular renin-angiotensin-aldosterone system (RAAS) has been found as a potential curative strategy. The RAAS contributes to glaucoma development through key effectors such as prorenin, angiotensin II, and aldosterone. Recent evidence has highlighted the potential of using RAAS modulators to combat glaucoma, yielding encouraging results. Our study aims to explore the molecular pathways linking the ocular RAAS and glaucoma, summarizing recent advances that elucidate the role of the RAAS in triggering oxidative stress, inflammation, and remodelling in the pathogenesis of glaucoma. Additionally, we will present emerging therapeutic approaches that utilize RAAS modulators and antioxidants to slow the progression of glaucoma.
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Affiliation(s)
- Francesco Buonfiglio
- Departments of Ophthalmology, University Medical Center of the Johannes Gutenberg- University, Langenbeckstr.1, 55131 Mainz, Germany.
| | - Norbert Pfeiffer
- Departments of Ophthalmology, University Medical Center of the Johannes Gutenberg- University, Langenbeckstr.1, 55131 Mainz, Germany.
| | - Adrian Gericke
- Departments of Ophthalmology, University Medical Center of the Johannes Gutenberg- University, Langenbeckstr.1, 55131 Mainz, Germany.
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8
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Tawengi M, Al-Dali Y, Tawengi A, Benter IF, Akhtar S. Targeting the epidermal growth factor receptor (EGFR/ErbB) for the potential treatment of renal pathologies. Front Pharmacol 2024; 15:1394997. [PMID: 39234105 PMCID: PMC11373609 DOI: 10.3389/fphar.2024.1394997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Accepted: 07/29/2024] [Indexed: 09/06/2024] Open
Abstract
Epidermal growth factor receptor (EGFR), which is referred to as ErbB1/HER1, is the prototype of the EGFR family of receptor tyrosine kinases which also comprises ErbB2 (Neu, HER2), ErbB3 (HER3), and ErbB4 (HER4). EGFR, along with other ErbBs, is expressed in the kidney tubules and is physiologically involved in nephrogenesis and tissue repair, mainly following acute kidney injury. However, its sustained activation is linked to several kidney pathologies, including diabetic nephropathy, hypertensive nephropathy, glomerulonephritis, chronic kidney disease, and renal fibrosis. This review aims to provide a summary of the recent findings regarding the consequences of EGFR activation in several key renal pathologies. We also discuss the potential interplay between EGFR and the reno-protective angiotensin-(1-7) (Ang-(1-7), a heptapeptide member of the renin-angiotensin-aldosterone system that counter-regulates the actions of angiotensin II. Ang-(1-7)-mediated inhibition of EGFR transactivation might represent a potential mechanism of action for its renoprotection. Our review suggests that there is a significant body of evidence supporting the potential inhibition of EGFR/ErbB, and/or administration of Ang-(1-7), as potential novel therapeutic strategies in the treatment of renal pathologies. Thus, EGFR inhibitors such as Gefitinib and Erlinotib that have an acceptable safety profile and have been clinically used in cancer chemotherapy since their FDA approval in the early 2000s, might be considered for repurposing in the treatment of renal pathologies.
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Affiliation(s)
- Mohamed Tawengi
- College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Yazan Al-Dali
- College of Medicine, QU Health, Qatar University, Doha, Qatar
| | | | - Ibrahim F Benter
- Faculty of Pharmacy, Final International University, Kyrenia, Cyprus
| | - Saghir Akhtar
- College of Medicine, QU Health, Qatar University, Doha, Qatar
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9
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Patel SN, Kulkarni K, Faisal T, Hussain T. Angiotensin-II type 2 receptor-mediated renoprotection is independent of receptor Mas in obese Zucker rats fed high-sodium diet. Front Pharmacol 2024; 15:1409313. [PMID: 39135807 PMCID: PMC11317439 DOI: 10.3389/fphar.2024.1409313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 06/27/2024] [Indexed: 08/15/2024] Open
Abstract
The consumption of a high-sodium diet (HSD) is injurious and known to elevate blood pressure (BP), especially in obesity. Acute infusion studies depict a functional interdependency between angiotensin-II type 2 receptor (AT2R) and receptor Mas (MasR). Hence, we hypothesize that the subacute blockade of MasR should reverse AT2R-mediated renoprotection in obese Zucker rats (OZRs). Male OZRs were fed an HSD (for 14 days) and treated with the AT2R agonist C21 (100 ng/min) without or with a MasR antagonist A779 (1,000 ng/min). The indices of oxidative stress, proteinuria, kidney injury, and BP were measured before and after, along with the terminal measurements of an array of inflammatory and kidney injury markers. The HSD significantly decreased the estimated glomerular filtration rate and urinary osmolality and increased thirst, diuresis, natriuresis, kaliuresis, plasma creatinine, urinary excretion of H2O2, proteinuria, renal expression and urinary excretion of kidney injury markers (NGAL and KIM-1), and BP indexes. The HSD feeding showed early changes in the renal expression of CRP, ICAM-1, and galectin-1. The C21 treatment prevented these pathological changes. The MasR antagonist A779 attenuated C21-mediated effects on the urinary excretion and renal expression of NGAL and oxidative stress in the absence of inflammation and BP changes. Overall, we conclude that the subacute functional interactions between AT2R and MasR are weak or transient and that the beneficial effects of AT2R activation are independent of the MasR blockade in the kidney of male obese rats fed an HSD.
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Affiliation(s)
| | | | | | - Tahir Hussain
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, United States
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Samuel CS, Li Y, Wang Y, Widdop RE. Functional crosstalk between angiotensin receptors (types 1 and 2) and relaxin family peptide receptor 1 (RXFP1): Implications for the therapeutic targeting of fibrosis. Br J Pharmacol 2024; 181:2302-2318. [PMID: 36560925 DOI: 10.1111/bph.16019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 12/15/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
Class A, rhodopsin-like, G-protein-coupled receptors (GPCRs) are by far the largest class of GPCRs and are integral membrane proteins used by various cells to convert extracellular signals into intracellular responses. Initially, class A GPCRs were believed to function as monomers, but a growing body of evidence has emerged to suggest that these receptors can function as homodimers and heterodimers and can undergo functional crosstalk to influence the actions of agonists or antagonists acting at each receptor. This review will focus on the angiotensin type 1 (AT1) and type 2 (AT2) receptors, as well as the relaxin family peptide receptor 1 (RXFP1), each of which have their unique characteristics but have been demonstrated to undergo some level of interaction when appropriately co-expressed, which influences the function of each receptor. In particular, this receptor functional crosstalk will be discussed in the context of fibrosis, the tissue scarring that results from a failed wound-healing response to injury, and which is a hallmark of chronic disease and related organ dysfunction. LINKED ARTICLES: This article is part of a themed issue Therapeutic Targeting of G Protein-Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc.
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Affiliation(s)
- Chrishan S Samuel
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia
- Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Yifang Li
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia
| | - Yan Wang
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia
| | - Robert E Widdop
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia
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Etebar N, Naderpour S, Akbari S, Zali A, Akhlaghdoust M, Daghighi SM, Baghani M, Sefat F, Hamidi SH, Rahimzadegan M. Impacts of SARS-CoV-2 on brain renin angiotensin system related signaling and its subsequent complications on brain: A theoretical perspective. J Chem Neuroanat 2024; 138:102423. [PMID: 38705215 DOI: 10.1016/j.jchemneu.2024.102423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 04/08/2024] [Accepted: 04/18/2024] [Indexed: 05/07/2024]
Abstract
Cellular ACE2 (cACE2), a vital component of the renin-angiotensin system (RAS), possesses catalytic activity to maintain AngII and Ang 1-7 balance, which is necessary to prevent harmful effects of AngII/AT2R and promote protective pathways of Ang (1-7)/MasR and Ang (1-7)/AT2R. Hemostasis of the brain-RAS is essential for maintaining normal central nervous system (CNS) function. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a viral disease that causes multi-organ dysfunction. SARS-CoV-2 mainly uses cACE2 to enter the cells and cause its downregulation. This, in turn, prevents the conversion of Ang II to Ang (1-7) and disrupts the normal balance of brain-RAS. Brain-RAS disturbances give rise to one of the pathological pathways in which SARS-CoV-2 suppresses neuroprotective pathways and induces inflammatory cytokines and reactive oxygen species. Finally, these impairments lead to neuroinflammation, neuronal injury, and neurological complications. In conclusion, the influence of RAS on various processes within the brain has significant implications for the neurological manifestations associated with COVID-19. These effects include sensory disturbances, such as olfactory and gustatory dysfunctions, as well as cerebrovascular and brain stem-related disorders, all of which are intertwined with disruptions in the RAS homeostasis of the brain.
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Affiliation(s)
- Negar Etebar
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Faculty of Pharmacy - Eastern Mediterranean University Famagusta, North Cyprus via Mersin 10, Turkey
| | - Saghi Naderpour
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Faculty of Pharmacy - Eastern Mediterranean University Famagusta, North Cyprus via Mersin 10, Turkey
| | - Setareh Akbari
- Neuroscience and Research Committee, School of Advanced Technology in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Alireza Zali
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Meisam Akhlaghdoust
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran; USERN Office, Functional Neurosurgery Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Mojtaba Daghighi
- Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Matin Baghani
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farshid Sefat
- Department of Biomedical Engineering, School of Engineering, University of Bradford, Bradford, UK
| | - Seyed Hootan Hamidi
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Acharya BM Reddy College of Pharmacy, Rajiv Gandhi University of Health Sciences, Bangalore, India
| | - Milad Rahimzadegan
- Functional Neurosurgery Research Center, Shohada Tajrish Comprehensive Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Gekle M, Eckenstaler R, Braun H, Olgac A, Robaa D, Mildenberger S, Dubourg V, Schreier B, Sippl W, Benndorf R. Direct GPCR-EGFR interaction enables synergistic membrane-to-nucleus information transfer. Cell Mol Life Sci 2024; 81:272. [PMID: 38900158 PMCID: PMC11335197 DOI: 10.1007/s00018-024-05281-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 04/12/2024] [Accepted: 05/14/2024] [Indexed: 06/21/2024]
Abstract
We addressed the heteromerization of the epidermal growth factor receptor (EGFR) with G-protein coupled receptors (GPCR) on the basis of angiotensin-II-receptor-subtype-1(AT1R)-EGFR interaction as proof-of-concept and show its functional relevance during synergistic nuclear information transfer, beyond ligand-dependent EGFR transactivation. Following in silico modelling, we generated EGFR-interaction deficient AT1R-mutants and compared them to AT1R-wildtype. Receptor interaction was assessed by co-immunoprecipitation (CoIP), Förster resonance energy transfer (FRET) and fluorescence-lifetime imaging microscopy (FLIM). Changes in cell morphology, ERK1/2-phosphorylation (ppERK1/2), serum response factor (SRF)-activation and cFOS protein expression were determined by digital high content microscopy at the single cell level. FRET, FLIM and CoIP confirmed the physical interaction of AT1R-wildtype with EGFR that was strongly reduced for the AT1R-mutants. Responsiveness of cells transfected with AT1R-WT or -mutants to angiotensin II or EGF was similar regarding changes in cell circularity, ppERK1/2 (direct and by ligand-dependent EGFR-transactivation), cFOS-expression and SRF-activity. By contrast, the EGFR-AT1R-synergism regarding these parameters was completely absent for in the interaction-deficient AT1R mutants. The results show that AT1R-EGFR heteromerisation enables AT1R-EGFR-synergism on downstream gene expression regulation, modulating the intensity and the temporal pattern of nuclear AT1R/EGFR-information transfer. Furthermore, remote EGFR transactivation, via ligand release or cytosolic tyrosine kinases, is not sufficient for the complete synergistic control of gene expression.
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Affiliation(s)
- Michael Gekle
- Julius-Bernstein-Institute of Physiology, Martin Luther University Halle-Wittenberg, 06112, Halle (Saale), Germany.
| | - Robert Eckenstaler
- Institute of Pharmacy, Department of Clinical Pharmacy and Pharmacotherapy, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Heike Braun
- Institute of Pharmacy, Department of Clinical Pharmacy and Pharmacotherapy, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Abdurrahman Olgac
- Institute of Pharmacy, Department of Medical Chemistry, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Dina Robaa
- Institute of Pharmacy, Department of Medical Chemistry, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Sigrid Mildenberger
- Julius-Bernstein-Institute of Physiology, Martin Luther University Halle-Wittenberg, 06112, Halle (Saale), Germany
| | - Virginie Dubourg
- Julius-Bernstein-Institute of Physiology, Martin Luther University Halle-Wittenberg, 06112, Halle (Saale), Germany
| | - Barbara Schreier
- Julius-Bernstein-Institute of Physiology, Martin Luther University Halle-Wittenberg, 06112, Halle (Saale), Germany
| | - Wolfgang Sippl
- Institute of Pharmacy, Department of Medical Chemistry, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Ralf Benndorf
- Institute of Pharmacy, Department of Clinical Pharmacy and Pharmacotherapy, Martin Luther University Halle-Wittenberg, Halle, Germany
- Institute of Pharmacology and Toxicology, Ruhr-University Bochum, 44780, Bochum, Germany
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Derkachev IA, Popov SV, Maslov LN, Mukhomedzyanov AV, Naryzhnaya NV, Gorbunov AS, Kan A, Krylatov AV, Podoksenov YK, Stepanov IV, Gusakova SV, Fu F, Pei JM. Angiotensin 1-7 increases cardiac tolerance to ischemia/reperfusion and mitigates adverse remodeling of the heart-The signaling mechanism. Fundam Clin Pharmacol 2024; 38:489-501. [PMID: 38311344 DOI: 10.1111/fcp.12983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 12/06/2023] [Accepted: 01/08/2024] [Indexed: 02/10/2024]
Abstract
BACKGROUND The high mortality rate of patients with acute myocardial infarction (AMI) remains the most pressing issue of modern cardiology. Over the past 10 years, there has been no significant reduction in mortality among patients with AMI. It is quite obvious that there is an urgent need to develop fundamentally new drugs for the treatment of AMI. Angiotensin 1-7 has some promise in this regard. OBJECTIVE The objective of this article is analysis of published data on the cardioprotective properties of angiotensin 1-7. METHODS PubMed, Scopus, Science Direct, and Google Scholar were used to search articles for this study. RESULTS Angiotensin 1-7 increases cardiac tolerance to ischemia/reperfusion and mitigates adverse remodeling of the heart. Angiotensin 1-7 can prevent not only ischemic but also reperfusion cardiac injury. The activation of the Mas receptor plays a key role in these effects of angiotensin 1-7. Angiotensin 1-7 alleviates Ca2+ overload of cardiomyocytes and reactive oxygen species production in ischemia/reperfusion (I/R) of the myocardium. It is possible that both effects are involved in angiotensin 1-7-triggered cardiac tolerance to I/R. Furthermore, angiotensin 1-7 inhibits apoptosis of cardiomyocytes and stimulates autophagy of cells. There is also indirect evidence suggesting that angiotensin 1-7 inhibits ferroptosis in cardiomyocytes. Moreover, angiotensin 1-7 possesses anti-inflammatory properties, possibly achieved through NF-kB activity inhibition. Phosphoinositide 3-kinase, Akt, and NO synthase are involved in the infarct-reducing effect of angiotensin 1-7. However, the specific end-effector of the cardioprotective impact of angiotensin 1-7 remains unknown. CONCLUSION The molecular nature of the end-effector of the infarct-limiting effect of angiotensin 1-7 has not been elucidated. Perhaps, this end-effector is the sarcolemmal KATP channel or the mitochondrial KATP channel.
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Affiliation(s)
- Ivan A Derkachev
- Laboratory of Experimental Cardiology, Cardiology Research Institute, Tomsk NRMC, Tomsk, Russia
| | - Sergey V Popov
- Laboratory of Experimental Cardiology, Cardiology Research Institute, Tomsk NRMC, Tomsk, Russia
| | - Leonid N Maslov
- Laboratory of Experimental Cardiology, Cardiology Research Institute, Tomsk NRMC, Tomsk, Russia
| | | | - Natalia V Naryzhnaya
- Laboratory of Experimental Cardiology, Cardiology Research Institute, Tomsk NRMC, Tomsk, Russia
| | - Alexander S Gorbunov
- Laboratory of Experimental Cardiology, Cardiology Research Institute, Tomsk NRMC, Tomsk, Russia
| | - Artur Kan
- Laboratory of Experimental Cardiology, Cardiology Research Institute, Tomsk NRMC, Tomsk, Russia
| | - Andrey V Krylatov
- Laboratory of Experimental Cardiology, Cardiology Research Institute, Tomsk NRMC, Tomsk, Russia
| | - Yuri K Podoksenov
- Laboratory of Experimental Cardiology, Cardiology Research Institute, Tomsk NRMC, Tomsk, Russia
| | - Ivan V Stepanov
- Laboratory of Experimental Cardiology, Cardiology Research Institute, Tomsk NRMC, Tomsk, Russia
| | - Svetlana V Gusakova
- Department of Biophysics and Functional Diagnostics, Siberian State Medical University, Tomsk, Russia
| | - Feng Fu
- Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, School of Basic Medicine, The Fourth Military Medical University, Xi'an, China
| | - Jian-Ming Pei
- Department of Physiology and Pathophysiology, National Key Discipline of Cell Biology, School of Basic Medicine, The Fourth Military Medical University, Xi'an, China
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14
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Schaich CL, Leisman DE, Goldberg MB, Filbin MR, Khanna AK, Chappell MC. Dysfunction of the renin-angiotensin-aldosterone system in human septic shock. Peptides 2024; 176:171201. [PMID: 38555976 PMCID: PMC11060897 DOI: 10.1016/j.peptides.2024.171201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 03/20/2024] [Accepted: 03/27/2024] [Indexed: 04/02/2024]
Abstract
Sepsis and septic shock are global healthcare problems associated with mortality rates of up to 40% despite optimal standard-of-care therapy and constitute the primary cause of death in intensive care units worldwide. Circulating biomarkers of septic shock severity may represent a clinically relevant approach to individualize those patients at risk for worse outcomes early in the course of the disease, which may facilitate early and more precise interventions to improve the clinical course. However, currently used septic shock biomarkers, including lactate, may be non-specific and have variable impact on prognosis and/or disease management. Activation of the renin-angiotensin-aldosterone system (RAAS) is likely an early event in septic shock, and studies suggest that an elevated level of renin, the early and committed step in the RAAS cascade, is a better predictor of worse outcomes in septic shock, including mortality, than the current standard-of-care measure of lactate. Despite a robust increase in renin, other elements of the RAAS, including endogenous levels of Ang II, may fail to sufficiently increase to maintain blood pressure, tissue perfusion, and protective immune responses in septic shock patients. We review the current clinical literature regarding the dysfunction of the RAAS in septic shock and potential therapeutic approaches to improve clinical outcomes.
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Affiliation(s)
- Christopher L Schaich
- Hypertension & Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Daniel E Leisman
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Marcia B Goldberg
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Micheal R Filbin
- Department of Emergency Medicine, Massachusetts General Hospital,Boston, MA, USA
| | - Ashish K Khanna
- Hypertension & Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Department of Anesthesiology, Section on Critical Care Medicine, Atrium Health Wake Forest Baptist Medical Center, USA; Outcomes Research Consortium, Cleveland, OH, USA
| | - Mark C Chappell
- Hypertension & Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
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15
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Barone M. Angiotensin-converting enzyme 2 and AMPK/mTOR pathway in the treatment of liver fibrosis: Should we consider further implications? World J Gastroenterol 2024; 30:2391-2396. [PMID: 38764773 PMCID: PMC11099390 DOI: 10.3748/wjg.v30.i18.2391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 03/09/2024] [Accepted: 04/17/2024] [Indexed: 05/11/2024] Open
Abstract
This editorial contains comments on the article by Zhao et al in print in the World Journal of Gastroenterology. The mechanisms responsible for hepatic fibrosis are also involved in cancerogenesis. Here, we recapitulated the complexity of the renin-angiotensin system, discussed the role of hepatic stellate cell (HSC) autophagy in liver fibrogenesis, and analyzed the possible implications in the development of hepatocarcinoma (HCC). Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers definitively contribute to reducing hepatic fibrogenesis, whereas their involvement in HCC is more evident in experimental conditions than in human studies. Angiotensin-converting enzyme 2 (ACE2), and its product Angiotensin (Ang) 1-7, not only regulate HSC autophagy and liver fibrosis, but they also represent potential targets for unexplored applications in the field of HCC. Finally, ACE2 overexpression inhibits HSC autophagy through the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway. In this case, Ang 1-7 acts binding to the MasR, and its agonists could modulate this pathway. However, since AMPK utilizes different targets to suppress the mTOR downstream complex mTOR complex 1 effectively, we still need to unravel the entire pathway to identify other potential targets for the therapy of fibrosis and liver cancer.
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Affiliation(s)
- Michele Barone
- Section of Gastroenterology, Department of Precision and Regenerative Medicine - Jonian Area- University of Bari, Bari 70124, Italy
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16
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Gironacci MM, Bruna-Haupt E. Unraveling the crosstalk between renin-angiotensin system receptors. Acta Physiol (Oxf) 2024; 240:e14134. [PMID: 38488216 DOI: 10.1111/apha.14134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 02/23/2024] [Accepted: 03/05/2024] [Indexed: 04/24/2024]
Abstract
The renin-angiotensin system (RAS) plays a key role in blood pressure regulation. The RAS is a complex interconnected system composed of two axes with opposite effects. The pressor arm, represented by angiotensin (Ang) II and the AT1 receptor (AT1R), mediates the vasoconstrictor, proliferative, hypertensive, oxidative, and pro-inflammatory effects of the RAS, while the depressor/protective arm, represented by Ang-(1-7), its Mas receptor (MasR) and the AT2 receptor (AT2R), opposes the actions elicited by the pressor arm. The AT1R, AT2R, and MasR belong to the G-protein-coupled receptor (GPCR) family. GPCRs operate not only as monomers, but they can also function in dimeric (homo and hetero) or higher-order oligomeric states. Due to the interaction with other receptors, GPCR properties may change: receptor affinity, trafficking, signaling, and its biological function may be altered. Thus, heteromerization provides a newly recognized means of modulation of receptor function, as well as crosstalk between GPCRs. This review is focused on angiotensin receptors, and how their properties are influenced by crosstalk with other receptors, adding more complexity to an already complex system and potentially opening up new therapeutic approaches.
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Affiliation(s)
- Mariela M Gironacci
- Facultad de Farmacia y Bioquímica, IQUIFIB (UBA-CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Ezequiel Bruna-Haupt
- INTEQUI (CONICET), Departamento de Química, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis, Argentina
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Abstract
The renin-angiotensin system is the most important peptide hormone system in the regulation of cardiovascular homeostasis. Its classical arm consists of the enzymes, renin, and angiotensin-converting enzyme, generating angiotensin II from angiotensinogen, which activates its AT1 receptor, thereby increasing blood pressure, retaining salt and water, and inducing cardiovascular hypertrophy and fibrosis. However, angiotensin II can also activate a second receptor, the AT2 receptor. Moreover, the removal of the C-terminal phenylalanine from angiotensin II by ACE2 (angiotensin-converting enzyme 2) yields angiotensin-(1-7), and this peptide interacts with its receptor Mas. When the aminoterminal Asp of angiotensin-(1-7) is decarboxylated, alamandine is generated, which activates the Mas-related G-protein-coupled receptor D, MrgD (Mas-related G-protein-coupled receptor type D). Since Mas, MrgD, and the AT2 receptor have opposing effects to the classical AT1 receptor, they and the enzymes and peptides activating them are called the alternative or protective arm of the renin-angiotensin system. This review will cover the historical aspects and the current standing of this recent addition to the biology of the renin-angiotensin system.
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Affiliation(s)
- Michael Bader
- Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
- Charité - University Medicine, Berlin, Germany
- Institute for Biology, University of Lübeck, Lübeck, Germany
| | - U. Muscha Steckelings
- Institute for Molecular Medicine, Dept. of Cardiovascular & Renal Research, University of Southern Denmark, Odense, Denmark
| | - Natalia Alenina
- Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Robson A.S. Santos
- National Institute of Science and Technology in Nanobiopharmaceutics (Nanobiofar) - Department of Physiology and Biophysics, Institute of Biological Sciences - Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Carlos M. Ferrario
- Laboratory of Translational Hypertension, Department of Surgery, Wake Forest School of Medicine, Winston Salem, NC 27157, USA
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18
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Li X, Fu YH, Tong XW, Zhang YT, Shan YY, Xu YX, Pu SD, Gao XY. RAAS in diabetic retinopathy: mechanisms and therapies. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2024; 68:e230292. [PMID: 38652701 PMCID: PMC11081058 DOI: 10.20945/2359-4292-2023-0292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Accepted: 11/23/2023] [Indexed: 04/25/2024]
Abstract
Diabetic retinopathy (DR) is a complication of diabetes with a complex pathophysiology and multiple factors involved. Recently, it has been found that the upregulation of the renin-angiotensin-aldosterone system (RAAS) leads to overexpression of angiotensin II (Ang II), which induces oxidative stress, inflammation, and angiogenesis in the retina. Therefore, RAAS may be a promising therapeutic target in DR. Notably, RAAS inhibitors are often used in the treatment of hypertension. Still, the potential role and mechanism of DR must be further studied. In this review, we discuss and summarize the pathology and potential therapeutic goals of RAAS in DR.
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Affiliation(s)
- Xin Li
- First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Department of Endocrinology, Harbin, China
| | - Yu-Hong Fu
- First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Department of Endocrinology, Harbin, China
| | - Xue-Wei Tong
- First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Department of Endocrinology, Harbin, China
| | - Yi-Tong Zhang
- First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Department of Endocrinology, Harbin, China
| | - Yong-Yan Shan
- First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Department of Endocrinology, Harbin, China
| | - Yu-Xin Xu
- First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Department of Endocrinology, Harbin, China
| | - Sheng-Dan Pu
- First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Department of Endocrinology, Harbin, China
| | - Xin-Yuan Gao
- First Affiliated Hospital of Harbin Medical University, Harbin Medical University, Department of Endocrinology, Harbin, China,
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Labandeira-Garcia JL, Labandeira CM, Guerra MJ, Rodriguez-Perez AI. The role of the brain renin-angiotensin system in Parkinson´s disease. Transl Neurodegener 2024; 13:22. [PMID: 38622720 PMCID: PMC11017622 DOI: 10.1186/s40035-024-00410-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 03/22/2024] [Indexed: 04/17/2024] Open
Abstract
The renin-angiotensin system (RAS) was classically considered a circulating hormonal system that regulates blood pressure. However, different tissues and organs, including the brain, have a local paracrine RAS. Mutual regulation between the dopaminergic system and RAS has been observed in several tissues. Dysregulation of these interactions leads to renal and cardiovascular diseases, as well as progression of dopaminergic neuron degeneration in a major brain center of dopamine/angiotensin interaction such as the nigrostriatal system. A decrease in the dopaminergic function induces upregulation of the angiotensin type-1 (AT1) receptor activity, leading to recovery of dopamine levels. However, AT1 receptor overactivity in dopaminergic neurons and microglial cells upregulates the cellular NADPH-oxidase-superoxide axis and Ca2+ release, which mediate several key events in oxidative stress, neuroinflammation, and α-synuclein aggregation, involved in Parkinson's disease (PD) pathogenesis. An intraneuronal antioxidative/anti-inflammatory RAS counteracts the effects of the pro-oxidative AT1 receptor overactivity. Consistent with this, an imbalance in RAS activity towards the pro-oxidative/pro-inflammatory AT1 receptor axis has been observed in the substantia nigra and striatum of several animal models of high vulnerability to dopaminergic degeneration. Interestingly, autoantibodies against angiotensin-converting enzyme 2 and AT1 receptors are increased in PD models and PD patients and contribute to blood-brain barrier (BBB) dysregulation and nigrostriatal pro-inflammatory RAS upregulation. Therapeutic strategies addressed to the modulation of brain RAS, by AT1 receptor blockers (ARBs) and/or activation of the antioxidative axis (AT2, Mas receptors), may be neuroprotective for individuals with a high risk of developing PD or in prodromal stages of PD to reduce progression of the disease.
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Affiliation(s)
- Jose Luis Labandeira-Garcia
- Cellular and Molecular Neurobiology of Parkinson´S Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, 15782, Spain.
- Networking Research Center On Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
| | | | - Maria J Guerra
- Cellular and Molecular Neurobiology of Parkinson´S Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, 15782, Spain
- Networking Research Center On Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Ana I Rodriguez-Perez
- Cellular and Molecular Neurobiology of Parkinson´S Disease, Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, 15782, Spain.
- Networking Research Center On Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
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20
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Zhang QQ, Chen QS, Feng F, Cao X, Chen XF, Zhang H. Benzoylaconitine: A promising ACE2-targeted agonist for enhancing cardiac function in heart failure. Free Radic Biol Med 2024; 214:206-218. [PMID: 38369076 DOI: 10.1016/j.freeradbiomed.2024.02.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 01/23/2024] [Accepted: 02/10/2024] [Indexed: 02/20/2024]
Abstract
Benzoylaconitine is a natural product in the treatment of cardiovascular disease. However, its pharmacological effect, direct target protein, and molecular mechanisms for the treatment of heart failure are unclear. In this study, benzoylaconitine inhibited Ang II-induced cell hypertrophy and fibrosis in rat primary cardiomyocytes and rat fibroblasts, while attenuating cardiac function and cardiac remodeling in TAC mice. Using the limited proteolysis-mass spectrometry (LiP-MS) method, the angiotensin-converting enzyme 2 (ACE2) was confirmed as a direct binding target of benzoylaconitine for the treatment of heart failure. In ACE2-knockdown cells and ACE2-/- mice, benzoylaconitine failed to ameliorate cardiomyocyte hypertrophy, fibrosis, and heart failure. Online RNA-sequence analysis indicated p38/ERK-mediated mitochondrial reactive oxygen species (ROS) and nuclear factor kappa B (NF-κB) activation are the possible downstream molecular mechanisms for the effect of BAC-ACE2 interaction. Further studies in ACE2-knockdown cells and ACE2-/- mice suggested that benzoylaconitine targeted ACE2 to suppress p38/ERK-mediated mitochondrial ROS and NF-κB pathway activation. Our findings suggest that benzoylaconitine is a promising ACE2 agonist in regulating mitochondrial ROS release and inflammation activation to improve cardiac function in the treatment of heart failure.
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Affiliation(s)
- Qi-Qiang Zhang
- Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Qing-Shan Chen
- Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Fei Feng
- School of Pharmacy, Naval Medical University (Second Military Medical University), 325 Guohe Road, Shanghai, 200433, China
| | - Xiang Cao
- Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Xiao-Fei Chen
- School of Pharmacy, Naval Medical University (Second Military Medical University), 325 Guohe Road, Shanghai, 200433, China.
| | - Hai Zhang
- Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
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21
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Kim S, Mollaei P, Antony A, Magar R, Barati Farimani A. GPCR-BERT: Interpreting Sequential Design of G Protein-Coupled Receptors Using Protein Language Models. J Chem Inf Model 2024; 64:1134-1144. [PMID: 38340054 PMCID: PMC10900288 DOI: 10.1021/acs.jcim.3c01706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 01/29/2024] [Accepted: 01/29/2024] [Indexed: 02/12/2024]
Abstract
With the rise of transformers and large language models (LLMs) in chemistry and biology, new avenues for the design and understanding of therapeutics have been opened up to the scientific community. Protein sequences can be modeled as language and can take advantage of recent advances in LLMs, specifically with the abundance of our access to the protein sequence data sets. In this letter, we developed the GPCR-BERT model for understanding the sequential design of G protein-coupled receptors (GPCRs). GPCRs are the target of over one-third of Food and Drug Administration-approved pharmaceuticals. However, there is a lack of comprehensive understanding regarding the relationship among amino acid sequence, ligand selectivity, and conformational motifs (such as NPxxY, CWxP, and E/DRY). By utilizing the pretrained protein model (Prot-Bert) and fine-tuning with prediction tasks of variations in the motifs, we were able to shed light on several relationships between residues in the binding pocket and some of the conserved motifs. To achieve this, we took advantage of attention weights and hidden states of the model that are interpreted to extract the extent of contributions of amino acids in dictating the type of masked ones. The fine-tuned models demonstrated high accuracy in predicting hidden residues within the motifs. In addition, the analysis of embedding was performed over 3D structures to elucidate the higher-order interactions within the conformations of the receptors.
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Affiliation(s)
- Seongwon Kim
- Department
of Chemical Engineering, Carnegie Mellon
University, Pittsburgh, Pennsylvania 15213, United States
| | - Parisa Mollaei
- Department
of Mechanical Engineering, Carnegie Mellon
University, Pittsburgh, Pennsylvania 15213, United States
| | - Akshay Antony
- Department
of Mechanical Engineering, Carnegie Mellon
University, Pittsburgh, Pennsylvania 15213, United States
| | - Rishikesh Magar
- Department
of Mechanical Engineering, Carnegie Mellon
University, Pittsburgh, Pennsylvania 15213, United States
| | - Amir Barati Farimani
- Department
of Mechanical Engineering, Carnegie Mellon
University, Pittsburgh, Pennsylvania 15213, United States
- Department
of Biomedical Engineering, Carnegie Mellon
University, Pittsburgh, Pennsylvania 15213, United States
- Machine
Learning Department, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, United States
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22
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Bhullar SK, Dhalla NS. Adaptive and maladaptive roles of different angiotensin receptors in the development of cardiac hypertrophy and heart failure. Can J Physiol Pharmacol 2024; 102:86-104. [PMID: 37748204 DOI: 10.1139/cjpp-2023-0226] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/27/2023]
Abstract
Angiotensin II (Ang II) is formed by the action of angiotensin-converting enzyme (ACE) in the renin-angiotensin system. This hormone is known to induce cardiac hypertrophy and heart failure and its actions are mediated by the interaction of both pro- and antihypertrophic Ang II receptors (AT1R and AT2R). Ang II is also metabolized by ACE 2 to Ang-(1-7), which elicits the activation of Mas receptors (MasR) for inducing antihypertrophic actions. Since heart failure under different pathophysiological situations is preceded by adaptive and maladaptive cardiac hypertrophy, we have reviewed the existing literature to gain some information regarding the roles of AT1R, AT2R, and MasR in both acute and chronic conditions of cardiac hypertrophy. It appears that the activation of AT1R may be involved in the development of adaptive and maladaptive cardiac hypertrophy as well as subsequent heart failure because both ACE inhibitors and AT1R antagonists exert beneficial effects. On the other hand, the activation of both AT2R and MasR may prevent the occurrence of maladaptive cardiac hypertrophy and delay the progression of heart failure, and thus therapy with different activators of these antihypertrophic receptors under chronic pathological stages may prove beneficial. Accordingly, it is suggested that a great deal of effort should be made to develop appropriate activators of both AT2R and MasR for the treatment of heart failure subjects.
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Affiliation(s)
- Sukhwinder K Bhullar
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre and Department of Physiology and Pathophysiology, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada
| | - Naranjan S Dhalla
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre and Department of Physiology and Pathophysiology, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada
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23
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Deng Y, Ding W, Peng Q, Wang W, Duan R, Zhang Y. Advancement in Beneficial Effects of AVE 0991: A Brief Review. Mini Rev Med Chem 2024; 24:139-158. [PMID: 36998128 DOI: 10.2174/1389557523666230328134932] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 01/08/2023] [Accepted: 01/11/2023] [Indexed: 04/01/2023]
Abstract
AVE 0991, a non-peptide analogue of Angiotensin-(1-7) [Ang-(1-7)], is orally active and physiologically well tolerated. Several studies have demonstrated that AVE 0991 improves glucose and lipid metabolism, and contains anti-inflammatory, anti-apoptotic, anti-fibrosis, and anti-oxidant effects. Numerous preclinical studies have also reported that AVE 0991 appears to have beneficial effects on a variety of systemic diseases, including cardiovascular, liver, kidney, cancer, diabetes, and nervous system diseases. This study searched multiple literature databases, including PubMed, Web of Science, EMBASE, Google Scholar, Cochrane Library, and the ClinicalTrials.gov website from the establishment to October 2022, using AVE 0991 as a keyword. This literature search revealed that AVE 0991 could play different roles via various signaling pathways. However, the potential mechanisms of these effects need further elucidation. This review summarizes the benefits of AVE 0991 in several medical problems, including the COVID-19 pandemic. The paper also describes the underlying mechanisms of AVE 0991, giving in-depth insights and perspectives on the pharmaceutical value of AVE 0991 in drug discovery and development.
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Affiliation(s)
- Yang Deng
- School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Wangli Ding
- School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Qiang Peng
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China
| | - Wei Wang
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China
| | - Rui Duan
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China
| | - Yingdong Zhang
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China
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24
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Samra AI, Kamel AS, Abdallah DM, El Fattah MAA, Ahmed KA, El-Abhar HS. Preclinical Evidence for the Role of the Yin/Yang Angiotensin System Components in Autism Spectrum Disorder: A Therapeutic Target of Astaxanthin. Biomedicines 2023; 11:3156. [PMID: 38137376 PMCID: PMC10740500 DOI: 10.3390/biomedicines11123156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 10/27/2023] [Accepted: 10/31/2023] [Indexed: 12/24/2023] Open
Abstract
Autism spectrum disorder (ASD) prevalence is emerging with an unclear etiology, hindering effective therapeutic interventions. Recent studies suggest potential renin-angiotensin system (RAS) alterations in different neurological pathologies. However, its implications in ASD are unexplored. This research fulfills the critical gap by investigating dual arms of RAS and their interplay with Notch signaling in ASD, using a valproic acid (VPA) model and assessing astaxanthin's (AST) modulatory impacts. Experimentally, male pups from pregnant rats receiving either saline or VPA on gestation day 12.5 were divided into control and VPA groups, with subsequent AST treatment in a subset (postnatal days 34-58). Behavioral analyses, histopathological investigations, and electron microscopy provided insights into the neurobehavioral and structural changes induced by AST. Molecular investigations of male pups' cortices revealed that AST outweighs the protective RAS elements with the inhibition of the detrimental arm. This established the neuroprotective and anti-inflammatory axes of RAS (ACE2/Ang1-7/MasR) in the ASD context. The results showed that AST's normalization of RAS components and Notch signaling underscore a novel therapeutic avenue in ASD, impacting neuronal integrity and behavioral outcomes. These findings affirm the integral role of RAS in ASD and highlight AST's potential as a promising treatment intervention, inviting further neurological research implications.
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Affiliation(s)
- Ayat I. Samra
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt; (A.I.S.); (D.M.A.); (M.A.A.E.F.)
| | - Ahmed S. Kamel
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt; (A.I.S.); (D.M.A.); (M.A.A.E.F.)
| | - Dalaal M. Abdallah
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt; (A.I.S.); (D.M.A.); (M.A.A.E.F.)
| | - Mai A. Abd El Fattah
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt; (A.I.S.); (D.M.A.); (M.A.A.E.F.)
| | - Kawkab A. Ahmed
- Pathology Department, Faculty of Veterinary Medicine, Cairo University, Cairo 11562, Egypt;
| | - Hanan S. El-Abhar
- Pharmacology, Toxicology, and Biochemistry Department, Faculty of Pharmacy, Future University in Egypt (FUE), Cairo 11835, Egypt;
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25
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Garcia B, Zarbock A, Bellomo R, Legrand M. The alternative renin-angiotensin system in critically ill patients: pathophysiology and therapeutic implications. Crit Care 2023; 27:453. [PMID: 37986086 PMCID: PMC10662652 DOI: 10.1186/s13054-023-04739-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 11/14/2023] [Indexed: 11/22/2023] Open
Abstract
The renin-angiotensin system (RAS) plays a crucial role in regulating blood pressure and the cardio-renal system. The classical RAS, mainly mediated by angiotensin I, angiotensin-converting enzyme, and angiotensin II, has been reported to be altered in critically ill patients, such as those in vasodilatory shock. However, recent research has highlighted the role of some components of the counterregulatory axis of the classical RAS, termed the alternative RAS, such as angiotensin-converting Enzyme 2 (ACE2) and angiotensin-(1-7), or peptidases which can modulate the RAS like dipeptidyl-peptidase 3, in many critical situations. In cases of shock, dipeptidyl-peptidase 3, an enzyme involved in the degradation of angiotensin and opioid peptides, has been associated with acute kidney injury and mortality and preclinical studies have tested its neutralization. Angiotensin-(1-7) has been shown to prevent septic shock development and improve outcomes in experimental models of sepsis. In the context of experimental acute lung injury, ACE2 activity has demonstrated a protective role, and its inactivation has been associated with worsened lung function, leading to the use of active recombinant human ACE2, in preclinical and human studies. Angiotensin-(1-7) has been tested in experimental models of acute lung injury and in a recent randomized controlled trial for patients with COVID-19 related hypoxemia. Overall, the alternative RAS appears to have a role in the pathogenesis of disease in critically ill patients, and modulation of the alternative RAS may improve outcomes. Here, we review the available evidence regarding the methods of analysis of the RAS, pathophysiological disturbances of this system, and discuss how therapeutic manipulation may improve outcomes in the critically ill.
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Affiliation(s)
- Bruno Garcia
- Department of Anesthesia and Peri-Operative Care, Division of Critical Care Medicine, University of California, San Francisco (UCSF), San Francisco, CA, USA
- Department of Intensive Care, Centre Hospitalier Universitaire de Lille, Lille, France
- Experimental Laboratory of the Department of Intensive Care, Université Libre de Bruxelles, Brussels, Belgium
| | - Alexander Zarbock
- Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital of Münster, Münster, Germany
| | - Rinaldo Bellomo
- Department of Intensive Care, Austin Hospital, Melbourne, VIC, 3084, Australia
- Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Australia
- Department of Critical Care, Melbourne Medical School, University of Melbourne, Melbourne, VIC, Australia
| | - Matthieu Legrand
- Department of Anesthesia and Peri-Operative Care, Division of Critical Care Medicine, University of California, San Francisco (UCSF), San Francisco, CA, USA.
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26
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Awata WMC, Sousa AH, de Mello MMB, Dourado TMH, Pinheiro LC, Elias-Oliveira J, Rodrigues VF, Carlos D, Castro MM, Tirapelli CR. AT 1 receptors modulate ethanol-induced loss of anticontractile effect of perivascular adipose tissue. Biochem Pharmacol 2023; 217:115840. [PMID: 37783376 DOI: 10.1016/j.bcp.2023.115840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 09/28/2023] [Accepted: 09/29/2023] [Indexed: 10/04/2023]
Abstract
Ethanol consumption activates renin-angiotensin-aldosterone system (RAAS), which plays a major role in the pro-contractile and hypertensive effects linked to ethanol. We hypothesized that ethanol consumption induces loss of the anticontractile effect of perivascular adipose tissue (PVAT)through RAAS-mediated mechanisms. We examined the contribution of angiotensin II type 1 receptors (AT1R) to ethanol-induced PVAT dysfunction. With this purpose, male Wistar Hannover rats were treated with ethanol 20 % (in volume ratio) and/or losartan (antagonist of AT1R; 10 mg/kg/day, gavage) for 9 weeks. Losartan prevented the increase in blood pressure and the loss of the anticontractile effect of PVAT induced by ethanol consumption. PVAT dysfunction occurred after 3 and 9 weeks of treatment with ethanol in an endothelium-dependent manner. Blockade of AT1R prevented ethanol-induced reduction of adiponectin levels in PVAT from ethanol-treated rats. Functional assays revealed that ethanol impaired the anticontractile effect of PVAT-derived angiotensin (1-7) and endothelial nitric oxide (NO). In conclusion, AT1R are implicated in ethanol-induced loss of the anticontractile effect of PVAT. In PVAT, AT1R activation decreases the production of adiponectin, a PVAT-derived factor that promotes vasorelaxation in an endothelium-dependent manner. In the endothelium, AT1R favors the production of superoxide (O2•-) leading to a reduction in NO bioavailability. These responses impair the vasodilator action induced by PVAT-derived angiotensin (1-7), which occurs via Mas receptors located in endothelial cells. Ethanol-induced PVAT dysfunction favors vascular hypercontractility, a response that could contribute to the hypertensive state associated with ethanol consumption.
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Affiliation(s)
- Wanessa M C Awata
- Programa de Pós-Graduação em Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, São Paulo, Brazil; Laboratório de Farmacologia, Escola de Enfermagem de Ribeirão Preto, USP, Ribeirão Preto, São Paulo, Brazil
| | - Arthur H Sousa
- Programa de Pós-Graduação em Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, São Paulo, Brazil; Laboratório de Farmacologia, Escola de Enfermagem de Ribeirão Preto, USP, Ribeirão Preto, São Paulo, Brazil
| | - Marcela M B de Mello
- Programa de Pós-Graduação em Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Thales M H Dourado
- Programa de Pós-Graduação em Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, São Paulo, Brazil; Laboratório de Farmacologia, Escola de Enfermagem de Ribeirão Preto, USP, Ribeirão Preto, São Paulo, Brazil
| | - Lucas C Pinheiro
- Laboratório de Farmacologia, Escola de Enfermagem de Ribeirão Preto, USP, Ribeirão Preto, São Paulo, Brazil
| | - Jefferson Elias-Oliveira
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, USP, Ribeirão Preto, São Paulo, Brazil
| | - Vanessa F Rodrigues
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, USP, Ribeirão Preto, São Paulo, Brazil
| | - Daniela Carlos
- Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, USP, Ribeirão Preto, São Paulo, Brazil
| | - Michele M Castro
- Programa de Pós-Graduação em Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Carlos R Tirapelli
- Laboratório de Farmacologia, Escola de Enfermagem de Ribeirão Preto, USP, Ribeirão Preto, São Paulo, Brazil.
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27
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Colin M, Delaitre C, Foulquier S, Dupuis F. The AT 1/AT 2 Receptor Equilibrium Is a Cornerstone of the Regulation of the Renin Angiotensin System beyond the Cardiovascular System. Molecules 2023; 28:5481. [PMID: 37513355 PMCID: PMC10383525 DOI: 10.3390/molecules28145481] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 07/11/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023] Open
Abstract
The AT1 receptor has mainly been associated with the pathological effects of the renin-angiotensin system (RAS) (e.g., hypertension, heart and kidney diseases), and constitutes a major therapeutic target. In contrast, the AT2 receptor is presented as the protective arm of this RAS, and its targeting via specific agonists is mainly used to counteract the effects of the AT1 receptor. The discovery of a local RAS has highlighted the importance of the balance between AT1/AT2 receptors at the tissue level. Disruption of this balance is suggested to be detrimental. The fine tuning of this balance is not limited to the regulation of the level of expression of these two receptors. Other mechanisms still largely unexplored, such as S-nitrosation of the AT1 receptor, homo- and heterodimerization, and the use of AT1 receptor-biased agonists, may significantly contribute to and/or interfere with the settings of this AT1/AT2 equilibrium. This review will detail, through several examples (the brain, wound healing, and the cellular cycle), the importance of the functional balance between AT1 and AT2 receptors, and how new molecular pharmacological approaches may act on its regulation to open up new therapeutic perspectives.
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Affiliation(s)
- Mélissa Colin
- CITHEFOR, Université de Lorraine, F-54000 Nancy, France
- Department of Pharmacology and Toxicology, MHeNS-School for Mental Health and Neuroscience, Maastricht University, 6200 MD Maastricht, The Netherlands
| | | | - Sébastien Foulquier
- Department of Pharmacology and Toxicology, MHeNS-School for Mental Health and Neuroscience, Maastricht University, 6200 MD Maastricht, The Netherlands
- CARIM-School for Cardiovascular Diseases, Maastricht University, 6200 MD Maastricht, The Netherlands
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28
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Razi O, Teixeira AM, Tartibian B, Zamani N, Knechtle B. Respiratory issues in patients with multiple sclerosis as a risk factor during SARS-CoV-2 infection: a potential role for exercise. Mol Cell Biochem 2023; 478:1533-1559. [PMID: 36411399 PMCID: PMC9684932 DOI: 10.1007/s11010-022-04610-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 11/04/2022] [Indexed: 11/23/2022]
Abstract
Coronavirus disease-2019 (COVID-19) is associated with cytokine storm and is characterized by acute respiratory distress syndrome (ARDS) and pneumonia problems. The respiratory system is a place of inappropriate activation of the immune system in people with multiple sclerosis (MS), and this may cause damage to the lung and worsen both MS and infections.The concerns for patients with multiple sclerosis are because of an enhance risk of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The MS patients pose challenges in this pandemic situation, because of the regulatory defect of autoreactivity of the immune system and neurological and respiratory tract symptoms. In this review, we first indicate respiratory issues associated with both diseases. Then, the main mechanisms inducing lung damages and also impairing the respiratory muscles in individuals with both diseases is discussed. At the end, the leading role of physical exercise on mitigating respiratory issues inducing mechanisms is meticulously evaluated.
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Affiliation(s)
- Omid Razi
- Department of Exercise Physiology, Faculty of Physical Education and Sport Sciences, Razi University, Kermanshah, Iran
| | - Ana Maria Teixeira
- Research Center for Sport and Physical Activity, Faculty of Sport Sciences and Physical Education, University of Coimbra, Coimbra, Portugal
| | - Bakhtyar Tartibian
- Department of Exercise Physiology, Faculty of Physical Education and Sports Sciences, Allameh Tabataba’i University, Tehran, Iran
| | - Nastaran Zamani
- Department of Biology, Faculty of Science, Payame-Noor University, Tehran, Iran
| | - Beat Knechtle
- Institute of Primary Care, University of Zurich, Zurich, Switzerland
- Medbase St. Gallen Am Vadianplatz, Vadianstrasse 26, 9001 St. Gallen, Switzerland
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29
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Molaei A, Molaei E, Hayes AW, Karimi G. Mas receptor: a potential strategy in the management of ischemic cardiovascular diseases. Cell Cycle 2023; 22:1654-1674. [PMID: 37365840 PMCID: PMC10361149 DOI: 10.1080/15384101.2023.2228089] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 05/10/2023] [Accepted: 06/16/2023] [Indexed: 06/28/2023] Open
Abstract
MasR is a critical element in the RAS accessory pathway that protects the heart against myocardial infarction, ischemia-reperfusion injury, and pathological remodeling by counteracting the effects of AT1R. This receptor is mainly stimulated by Ang 1-7, which is a bioactive metabolite of the angiotensin produced by ACE2. MasR activation attenuates ischemia-related myocardial damage by facilitating vasorelaxation, improving cell metabolism, reducing inflammation and oxidative stress, inhibiting thrombosis, and stabilizing atherosclerotic plaque. It also prevents pathological cardiac remodeling by suppressing hypertrophy- and fibrosis-inducing signals. In addition, the potential of MasR in lowering blood pressure, improving blood glucose and lipid profiles, and weight loss has made it effective in modulating risk factors for coronary artery disease including hypertension, diabetes, dyslipidemia, and obesity. Considering these properties, the administration of MasR agonists offers a promising approach to the prevention and treatment of ischemic heart disease.Abbreviations: Acetylcholine (Ach); AMP-activated protein kinase (AMPK); Angiotensin (Ang); Angiotensin receptor (ATR); Angiotensin receptor blocker (ARB); Angiotensin-converting enzyme (ACE); Angiotensin-converting enzyme inhibitor (ACEI); Anti-PRD1-BF1-RIZ1 homologous domain containing 16 (PRDM16); bradykinin (BK); Calcineurin (CaN); cAMP-response element binding protein (CREB); Catalase (CAT); C-C Motif Chemokine Ligand 2 (CCL2); Chloride channel 3 (CIC3); c-Jun N-terminal kinases (JNK); Cluster of differentiation 36 (CD36); Cocaine- and amphetamine-regulated transcript (CART); Connective tissue growth factor (CTGF); Coronary artery disease (CAD); Creatine phosphokinase (CPK); C-X-C motif chemokine ligand 10 (CXCL10); Cystic fibrosis transmembrane conductance regulator (CFTR); Endothelial nitric oxide synthase (eNOS); Extracellular signal-regulated kinase 1/2 (ERK 1/2); Fatty acid transport protein (FATP); Fibroblast growth factor 21 (FGF21); Forkhead box protein O1 (FoxO1); Glucokinase (Gk); Glucose transporter (GLUT); Glycogen synthase kinase 3β (GSK3β); High density lipoprotein (HDL); High sensitive C-reactive protein (hs-CRP); Inositol trisphosphate (IP3); Interleukin (IL); Ischemic heart disease (IHD); Janus kinase (JAK); Kruppel-like factor 4 (KLF4); Lactate dehydrogenase (LDH); Left ventricular end-diastolic pressure (LVEDP); Left ventricular end-systolic pressure (LVESP); Lipoprotein lipase (LPL); L-NG-Nitro arginine methyl ester (L-NAME); Low density lipoprotein (LDL); Mammalian target of rapamycin (mTOR); Mas-related G protein-coupled receptors (Mrgpr); Matrix metalloproteinase (MMP); MAPK phosphatase-1 (MKP-1); Mitogen-activated protein kinase (MAPK); Monocyte chemoattractant protein-1 (MCP-1); NADPH oxidase (NOX); Neuropeptide FF (NPFF); Neutral endopeptidase (NEP); Nitric oxide (NO); Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB); Nuclear-factor of activated T-cells (NFAT); Pancreatic and duodenal homeobox 1 (Pdx1); Peroxisome proliferator- activated receptor γ (PPARγ); Phosphoinositide 3-kinases (PI3k); Phospholipase C (PLC); Prepro-orexin (PPO); Prolyl-endopeptidase (PEP); Prostacyclin (PGI2); Protein kinase B (Akt); Reactive oxygen species (ROS); Renin-angiotensin system (RAS); Rho-associated protein kinase (ROCK); Serum amyloid A (SAA); Signal transducer and activator of transcription (STAT); Sirtuin 1 (Sirt1); Slit guidance ligand 3 (Slit3); Smooth muscle 22α (SM22α); Sterol regulatory element-binding protein 1 (SREBP-1c); Stromal-derived factor-1a (SDF); Superoxide dismutase (SOD); Thiobarbituric acid reactive substances (TBARS); Tissue factor (TF); Toll-like receptor 4 (TLR4); Transforming growth factor β1 (TGF-β1); Tumor necrosis factor α (TNF-α); Uncoupling protein 1 (UCP1); Ventrolateral medulla (VLM).
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Affiliation(s)
- Ali Molaei
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Emad Molaei
- PharmD, Assistant of Clinical Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - A. Wallace Hayes
- University of South Florida College of Public Health, Tampa, Florida, USA
| | - Gholamreza Karimi
- Pharmaceutical Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmacodynamics and Toxicology, Faculty of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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30
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Zhang X, Zhang S, Wang M, Chen H, Liu H. Advances in the allostery of angiotensin II type 1 receptor. Cell Biosci 2023; 13:110. [PMID: 37330563 DOI: 10.1186/s13578-023-01063-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 05/31/2023] [Indexed: 06/19/2023] Open
Abstract
Angiotensin II type 1 receptor (AT1R) is a promising therapeutic target for cardiovascular diseases. Compared with orthosteric ligands, allosteric modulators attract considerable attention for drug development due to their unique advantages of high selectivity and safety. However, no allosteric modulators of AT1R have been applied in clinical trials up to now. Except for the classical allosteric modulators of AT1R such as antibody, peptides and amino acids, cholesterol and biased allosteric modulators, there are non-classical allosteric modes including the ligand-independent allosteric mode, and allosteric mode of biased agonists and dimers. In addition, finding the allosteric pockets based on AT1R conformational change and interaction interface of dimers are the future of drug design. In this review, we summarize the different allosteric mode of AT1R, with a view to contribute to the development and utilization of drugs targeting AT1R allostery.
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Affiliation(s)
- Xi Zhang
- Department of Physiology & Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, People's Republic of China
- Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Disease, Capital Medical University, Beijing, 100069, People's Republic of China
| | - Suli Zhang
- Department of Physiology & Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, People's Republic of China
- Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Disease, Capital Medical University, Beijing, 100069, People's Republic of China
| | - Meili Wang
- Department of Physiology & Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, People's Republic of China
- Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Disease, Capital Medical University, Beijing, 100069, People's Republic of China
| | - Hao Chen
- Department of Physiology & Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, People's Republic of China
- Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Disease, Capital Medical University, Beijing, 100069, People's Republic of China
| | - Huirong Liu
- Department of Physiology & Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, People's Republic of China.
- Beijing Key Laboratory of Metabolic Disorders Related Cardiovascular Disease, Capital Medical University, Beijing, 100069, People's Republic of China.
- Department of Physiology & Pathophysiology, School of Basic Medical Sciences, Capital Medical University, 10 Xitoutiao, You An Men Street, Beijing, 100069, China.
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31
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Chen H, Peng J, Wang T, Wen J, Chen S, Huang Y, Zhang Y. Counter-regulatory renin-angiotensin system in hypertension: Review and update in the era of COVID-19 pandemic. Biochem Pharmacol 2023; 208:115370. [PMID: 36481346 PMCID: PMC9721294 DOI: 10.1016/j.bcp.2022.115370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/26/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022]
Abstract
Cardiovascular disease is the major cause of mortality and disability, with hypertension being the most prevalent risk factor. Excessive activation of the renin-angiotensin system (RAS) under pathological conditions, leading to vascular remodeling and inflammation, is closely related to cardiovascular dysfunction. The counter-regulatory axis of the RAS consists of angiotensin-converting enzyme 2 (ACE2), angiotensin (1-7), angiotensin (1-9), alamandine, proto-oncogene Mas receptor, angiotensin II type-2 receptor and Mas-related G protein-coupled receptor member D. Each of these components has been shown to counteract the effects of the overactivated RAS. In this review, we summarize the latest insights into the complexity and interplay of the counter-regulatory RAS axis in hypertension, highlight the pathophysiological functions of ACE2, a multifunctional molecule linking hypertension and COVID-19, and discuss the function and therapeutic potential of targeting this counter-regulatory RAS axis to prevent and treat hypertension in the context of the current COVID-19 pandemic.
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Affiliation(s)
- Hongyin Chen
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen 518000, Guangdong, China
| | - Jiangyun Peng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, China,Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-sen Memorial Hospital, Foshan 528200, Guangdong, China
| | - Tengyao Wang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, China,Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-sen Memorial Hospital, Foshan 528200, Guangdong, China
| | - Jielu Wen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, China,Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-sen Memorial Hospital, Foshan 528200, Guangdong, China
| | - Sifan Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, China,Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-sen Memorial Hospital, Foshan 528200, Guangdong, China
| | - Yu Huang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China,Corresponding authors
| | - Yang Zhang
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen 518000, Guangdong, China,Corresponding authors
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A Review on COVID-19: Primary Receptor, Endothelial Dysfunction, Related Comorbidities, and Therapeutics. IRANIAN JOURNAL OF SCIENCE 2023. [PMCID: PMC9843681 DOI: 10.1007/s40995-022-01400-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Since December 2019, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a global pandemic named coronavirus disease-19 (COVID-19) and resulted in a worldwide economic crisis. Utilizing the spike-like protein on its surface, the SARS-CoV-2 binds to the receptor angiotensin-converting enzyme 2 (ACE2), which highly expresses on the surface of many cell types. Given the crucial role of ACE2 in the renin–angiotensin system, its engagement by SARS-CoV-2 could potentially result in endothelial cell perturbation. This is supported by the observation that one of the most common consequences of COVID-19 infection is endothelial dysfunction and subsequent vascular damage. Furthermore, endothelial dysfunction is the shared denominator among previous comorbidities, including hypertension, kidney disease, cardiovascular diseases, etc., which are associated with an increased risk of severe disease and mortality in COVID-19 patients. Several vaccines and therapeutics have been developed and suggested for COVID-19 therapy. The present review summarizes the relationship between ACE2 and endothelial dysfunction and COVID-19, also reviews the most common comorbidities associated with COVID-19, and finally reviews several categories of potential therapies against COVID-19.
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Rukavina Mikusic NL, Gironacci MM. Mas receptor endocytosis and signaling in health and disease. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 194:49-65. [PMID: 36631200 DOI: 10.1016/bs.pmbts.2022.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The renin angiotensin system (RAS) plays a major role in blood pressure regulation and electrolyte homeostasis and is mainly composed by two axes mediating opposite effects. The pressor axis, constituted by angiotensin (Ang) II and the Ang II type 1 receptor (AT1R), exerts vasoconstrictor, proliferative, hypertensive, oxidative and pro-inflammatory actions, while the depressor/protective axis, represented by Ang-(1-7), its Mas receptor (MasR) and the Ang II type 2 receptor (AT2R), opposes the actions elicited by the pressor arm. The MasR belongs to the G protein-coupled receptor (GPCR) family. To avoid receptor overstimulation, GPCRs undergo internalization and trafficking into the cell after being stimulated. Then, the receptor may induce other signaling cascades or it may even interact with other receptors, generating distinct biological responses. Thus, control of a GPCR regarding space and time affects the specificity of the signals transduced by the receptor and the ultimate cellular response. The present chapter is focused on the signaling and trafficking pathways of MasR under physiological conditions and its participation in the pathogenesis of numerous brain diseases.
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Affiliation(s)
- Natalia L Rukavina Mikusic
- From Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Dpto. Química Biológica, IQUIFIB (UBA-CONICET), Buenos Aires, Argentina
| | - Mariela M Gironacci
- From Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Dpto. Química Biológica, IQUIFIB (UBA-CONICET), Buenos Aires, Argentina.
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34
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Vieira TN, Saraiva ALL, Guimarães RM, Luiz JPM, Pinto LG, de Melo Rodrigues Ávila V, Goulart LR, Cunha-Junior JP, McNaughton PA, Cunha TM, Ferreira J, Silva CR. Angiotensin type 2 receptor antagonism as a new target to manage gout. Inflammopharmacology 2022; 30:2399-2410. [PMID: 36173505 DOI: 10.1007/s10787-022-01076-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 09/15/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND There is a growing search for therapeutic targets in the treatment of gout. The present study aimed to evaluate the analgesic and anti-inflammatory potential of angiotensin type 2 receptor (AT2R) antagonism in an acute gout attack mouse model. METHODS Male wild-type (WT) C57BL/6 mice either with the AT2R antagonist, PD123319 (10 pmol/joint), or with vehicle injections, or AT2R KO mice, received intra-articular (IA) injection of monosodium urate (MSU) crystals (100 µg/joint), that induce the acute gout attack, and were tested for mechanical allodynia, thermal hyperalgesia, spontaneous nociception and ankle edema development at several times after the injections. To test an involvement of AT2R in joint pain, mice received an IA administration of angiotensin II (0.05-5 nmol/joint) with or without PD123319, and were also evaluated for pain and edema development. Ankle joint tissue samples from mice undergoing the above treatments were assessed for myeloperoxidase activity, IL-1β release, mRNA expression analyses and nitrite/nitrate levels, 4 h after injections. RESULTS AT2R antagonism has robust antinociceptive effects on mechanical allodynia (44% reduction) and spontaneous nociception (56%), as well as anti-inflammatory effects preventing edema formation (45%), reducing myeloperoxidase activity (54%) and IL-1β levels (32%). Additionally, Agtr2tm1a mutant mice have largely reduced painful signs of gout. Angiotensin II administration causes pain and inflammation, which was prevented by AT2R antagonism, as observed in mechanical allodynia 4 h (100%), spontaneous nociception (46%), cold nociceptive response (54%), edema formation (83%), myeloperoxidase activity (48%), and IL-1β levels (89%). PD123319 treatment also reduces NO concentrations (74%) and AT2R mRNA levels in comparison with MSU untreated mice. CONCLUSION Our findings show that AT2R activation contributes to acute pain in experimental mouse models of gout. Therefore, the antagonism of AT2R may be a potential therapeutic option to manage gout arthritis.
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Affiliation(s)
- Thiago Neves Vieira
- Graduate Program in Genetics and Biochemistry, Institute of Biotechnology, Federal University of Uberlândia, Uberlândia, MG, 38408-100, Brazil
| | - André L Lopes Saraiva
- Graduate Program in Genetics and Biochemistry, Institute of Biotechnology, Federal University of Uberlândia, Uberlândia, MG, 38408-100, Brazil
| | - Rafaela Mano Guimarães
- Center for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - João Paulo Mesquita Luiz
- Center for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Larissa Garcia Pinto
- Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London, SE1 1UL, UK
| | - Veridiana de Melo Rodrigues Ávila
- Graduate Program in Genetics and Biochemistry, Institute of Biotechnology, Federal University of Uberlândia, Uberlândia, MG, 38408-100, Brazil
| | - Luiz Ricardo Goulart
- Graduate Program in Genetics and Biochemistry, Institute of Biotechnology, Federal University of Uberlândia, Uberlândia, MG, 38408-100, Brazil
| | - Jair Pereira Cunha-Junior
- Department of Immunology, Institute of Sciences Biomedical Sciences, Federal University of Uberlândia, Uberlândia, MG, 38405-318, Brazil
| | - Peter Anthony McNaughton
- Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London, SE1 1UL, UK
| | - Thiago Mattar Cunha
- Center for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Juliano Ferreira
- Graduated Program in Pharmacology, Pharmacology Department, Federal University of Santa Catarina (UFSC), Florianopolis, SC, 88049-900, Brazil
| | - Cassia Regina Silva
- Graduate Program in Genetics and Biochemistry, Institute of Biotechnology, Federal University of Uberlândia, Uberlândia, MG, 38408-100, Brazil.
- LABITOX, Post-Graduated Program in Genetics and Biochemistry, Biotechnology Institute, Federal University of Uberlândia, Av. Pará 1720-Campus Umuarama, Jardim Umuarama-Bloco 2E-Officeroom 224, Uberlândia, MG, 38408-100, Brazil.
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Sex Difference in MasR Expression and Functions in the Renal System. J Renin Angiotensin Aldosterone Syst 2022; 2022:1327839. [PMID: 36148474 PMCID: PMC9482541 DOI: 10.1155/2022/1327839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 08/10/2022] [Accepted: 08/17/2022] [Indexed: 11/17/2022] Open
Abstract
Renin-angiotensin system (RAS), as a critical system for controlling body fluid and hemostasis, contains peptides and receptors, including angiotensin 1-7 (Ang 1-7) and Mas receptor (MasR). Ang 1-7 implements its function via MasR. Ang II is another peptide in RAS that performs its actions via two Ang II type 1 and 2 receptors (AT1R and AT2R). The functions of AT2R and MasR are very similar, and both have a vasodilation effect, while AT1R has a vasoconstriction role. MasR affects many mechanisms in the brain, heart, blood vessels, kidney, lung, endocrine, reproductive, skeletal muscle, and liver and probably acts like a paracrine hormone in these organs. The effect of Ang 1-7 in the kidney is complex according to the hydroelectrolyte status, the renal sympathetic nervous system, and the activity level of the RAS. The MasR expression and function seem more complex than Ang II receptors and have interacted with Ang II receptors and many other factors, including sex hormones. Also, pathological conditions including hypertension, diabetes, and ischemia-reperfusion could change MasR expression and function. In this review, we consider the role of sex differences in MasR expression and functions in the renal system under physiological and pathological conditions.
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36
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Xiong Y, Ke R, Zhang Q, Lan W, Yuan W, Chan KNI, Roussel T, Jiang Y, Wu J, Liu S, Wong AST, Shim JS, Zhang X, Xie R, Dusetti N, Iovanna J, Habib N, Peng L, Lee LTO. Small Activating RNA Modulation of the G Protein-Coupled Receptor for Cancer Treatment. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2200562. [PMID: 35712764 PMCID: PMC9475523 DOI: 10.1002/advs.202200562] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 05/23/2022] [Indexed: 06/15/2023]
Abstract
G protein-coupled receptors (GPCRs) are the most common and important drug targets. However, >70% of GPCRs are undruggable or difficult to target using conventional chemical agonists/antagonists. Small nucleic acid molecules, which can sequence-specifically modulate any gene, offer a unique opportunity to effectively expand drug targets, especially those that are undruggable or difficult to address, such as GPCRs. Here, the authors report for the first time that small activating RNAs (saRNAs) effectively modulate a GPCR for cancer treatment. Specifically, saRNAs promoting the expression of Mas receptor (MAS1), a GPCR that counteracts the classical angiotensin II pathway in cancer cell proliferation and migration, are identified. These saRNAs, delivered by an amphiphilic dendrimer vector, enhance MAS1 expression, counteracting the angiotensin II/angiotensin II Receptor Type 1 axis, and leading to significant suppression of tumorigenesis and the inhibition of tumor progression of multiple cancers in tumor-xenografted mouse models and patient-derived tumor models. This study provides not only a new strategy for cancer therapy by targeting the renin-angiotensin system, but also a new avenue to modulate GPCR signaling by RNA activation.
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Affiliation(s)
- Yunfang Xiong
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
| | - Ran Ke
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
| | - Qingyu Zhang
- Department of Obstetrics and GynaecologyAffiliated Hospital of Guangdong Medical UniversityZhanjiangGuangdong524001China
| | - Wenjun Lan
- Aix Marseille UniversitéCNRSCentre Interdisciplinaire de Nanoscience de Marseille (UMR 7325)Equipe Labellisée Ligue Contre le CancerMarseille13288France
- Centre de Recherche en Cancérologie de Marseille (CRCM)INSERM U1068CNRSAix‐Marseille Université and Institut Paoli‐CalmettesMarseille13288France
| | - Wanjun Yuan
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
| | - Karol Nga Ieng Chan
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
| | - Tom Roussel
- Aix Marseille UniversitéCNRSCentre Interdisciplinaire de Nanoscience de Marseille (UMR 7325)Equipe Labellisée Ligue Contre le CancerMarseille13288France
| | - Yifan Jiang
- Aix Marseille UniversitéCNRSCentre Interdisciplinaire de Nanoscience de Marseille (UMR 7325)Equipe Labellisée Ligue Contre le CancerMarseille13288France
| | - Jing Wu
- Aix Marseille UniversitéCNRSCentre Interdisciplinaire de Nanoscience de Marseille (UMR 7325)Equipe Labellisée Ligue Contre le CancerMarseille13288France
| | - Shuai Liu
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
| | - Alice Sze Tsai Wong
- School of Biological SciencesThe University of Hong KongPokfulam RoadHong KongChina
| | - Joong Sup Shim
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
- MOE Frontiers Science Center for Precision OncologyUniversity of MacauTaipaMacau999078China
| | - Xuanjun Zhang
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
- MOE Frontiers Science Center for Precision OncologyUniversity of MacauTaipaMacau999078China
| | - Ruiyu Xie
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
- MOE Frontiers Science Center for Precision OncologyUniversity of MacauTaipaMacau999078China
| | - Nelson Dusetti
- Centre de Recherche en Cancérologie de Marseille (CRCM)INSERM U1068CNRSAix‐Marseille Université and Institut Paoli‐CalmettesMarseille13288France
| | - Juan Iovanna
- Centre de Recherche en Cancérologie de Marseille (CRCM)INSERM U1068CNRSAix‐Marseille Université and Institut Paoli‐CalmettesMarseille13288France
| | - Nagy Habib
- Department of Surgery and CancerImperial College LondonLondonW12 0NNUK
- MiNA Therapeutics, Translation & Innovation Hub80 Wood LaneLondonW12 0BZUK
| | - Ling Peng
- Aix Marseille UniversitéCNRSCentre Interdisciplinaire de Nanoscience de Marseille (UMR 7325)Equipe Labellisée Ligue Contre le CancerMarseille13288France
| | - Leo Tsz On Lee
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
- MOE Frontiers Science Center for Precision OncologyUniversity of MacauTaipaMacau999078China
- Centre of Reproduction, Development, and AgingFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
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Lin H, Geurts F, Hassler L, Batlle D, Mirabito Colafella KM, Denton KM, Zhuo JL, Li XC, Ramkumar N, Koizumi M, Matsusaka T, Nishiyama A, Hoogduijn MJ, Hoorn EJ, Danser AHJ. Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting. Pharmacol Rev 2022; 74:462-505. [PMID: 35710133 PMCID: PMC9553117 DOI: 10.1124/pharmrev.120.000236] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The concept of local formation of angiotensin II in the kidney has changed over the last 10-15 years. Local synthesis of angiotensinogen in the proximal tubule has been proposed, combined with prorenin synthesis in the collecting duct. Binding of prorenin via the so-called (pro)renin receptor has been introduced, as well as megalin-mediated uptake of filtered plasma-derived renin-angiotensin system (RAS) components. Moreover, angiotensin metabolites other than angiotensin II [notably angiotensin-(1-7)] exist, and angiotensins exert their effects via three different receptors, of which angiotensin II type 2 and Mas receptors are considered renoprotective, possibly in a sex-specific manner, whereas angiotensin II type 1 (AT1) receptors are believed to be deleterious. Additionally, internalized angiotensin II may stimulate intracellular receptors. Angiotensin-converting enzyme 2 (ACE2) not only generates angiotensin-(1-7) but also acts as coronavirus receptor. Multiple, if not all, cardiovascular diseases involve the kidney RAS, with renal AT1 receptors often being claimed to exert a crucial role. Urinary RAS component levels, depending on filtration, reabsorption, and local release, are believed to reflect renal RAS activity. Finally, both existing drugs (RAS inhibitors, cyclooxygenase inhibitors) and novel drugs (angiotensin receptor/neprilysin inhibitors, sodium-glucose cotransporter-2 inhibitors, soluble ACE2) affect renal angiotensin formation, thereby displaying cardiovascular efficacy. Particular in the case of the latter three, an important question is to what degree they induce renoprotection (e.g., in a renal RAS-dependent manner). This review provides a unifying view, explaining not only how kidney angiotensin formation occurs and how it is affected by drugs but also why drugs are renoprotective when altering the renal RAS. SIGNIFICANCE STATEMENT: Angiotensin formation in the kidney is widely accepted but little understood, and multiple, often contrasting concepts have been put forward over the last two decades. This paper offers a unifying view, simultaneously explaining how existing and novel drugs exert renoprotection by interfering with kidney angiotensin formation.
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Affiliation(s)
- Hui Lin
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Frank Geurts
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Luise Hassler
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Daniel Batlle
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Katrina M Mirabito Colafella
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Kate M Denton
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Jia L Zhuo
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Xiao C Li
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Nirupama Ramkumar
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Masahiro Koizumi
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Taiji Matsusaka
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Akira Nishiyama
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Martin J Hoogduijn
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Ewout J Hoorn
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - A H Jan Danser
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
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Initial Angiotensin Receptor Blocker Response in Young Marfan Patients Decreases After 3 Years of Treatment. Pediatr Cardiol 2022; 43:586-595. [PMID: 34757469 PMCID: PMC8933348 DOI: 10.1007/s00246-021-02761-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Accepted: 10/21/2021] [Indexed: 11/28/2022]
Abstract
Marfan syndrome is caused by mutations of the fibrillin-1 gene, which weakens the connective tissue integrity. Since 2003, bioavailability regulations of TGF-ß through fibrillin alterations have been presumed of being the culprit mechanisms for aortic aneurysm development. We present the analysis of our single-center Marfan children and adolescents cohort to assess the influence of age, sex, degree of cardiovascular involvement and dosage on losartan effectivity. This prospective longitudinal registered echocardiographical investigation (EudraCT 2009-016139-36) of 49 patients with an average follow-up of 72 months focused on aortic root z-scores, elasticity, and yearly progression rates. The 33 patients under medication with losartan showed an aortic root z-score reduction during the first 36 months compared to 22 patients without medication presenting constant mild progression. Yet, results diminished under losartan thereafter, adding up to similar progressions over 72 months in both groups (0.07 ± 0.10/year versus 0.04 ± 0.11/year). Although male patients exhibited higher root z-scores, progression with and without medication was comparable to females and not age-dependent. In conclusion, losartan evoked a significant aortic root z-score regression in young Marfan patients over the first 3 years, but this effect mitigated thereafter. The initial improvement concurred with ameliorated elasticity; lower stiffness levels predicted better clinical outcome, but likewise only up to 36 months. Sex differences in dilatation severity were observed but neither age nor sex had significant influence on progression rates. Losartan dosages were gradually increased in more severely affected patients and provided an equal rate of root progression over 72 months in comparison to patients under losartan treatment with lesser baseline dilatation severity.
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Zaidan I, Tavares LP, Sugimoto MA, Lima KM, Negreiros-Lima GL, Teixeira LC, Miranda TC, Valiate BV, Cramer A, Vago JP, Campolina-Silva GH, Souza JA, Grossi LC, Pinho V, Campagnole-Santos MJ, Santos RAS, Teixeira MM, Galvão I, Sousa LP. Angiotensin-(1-7)/MasR axis promotes migration of monocytes/macrophages with a regulatory phenotype to perform phagocytosis and efferocytosis. JCI Insight 2021; 7:147819. [PMID: 34874920 PMCID: PMC8765051 DOI: 10.1172/jci.insight.147819] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 11/24/2021] [Indexed: 11/17/2022] Open
Abstract
Nonphlogistic migration of macrophages contributes to the clearance of pathogens and apoptotic cells, a critical step for the resolution of inflammation and return to homeostasis. Angiotensin-(1-7) [Ang-(1-7)] is a heptapeptide of the renin-angiotensin system that acts through Mas receptor (MasR). Ang-(1-7) has recently emerged as a novel proresolving mediator, yet Ang-(1-7) resolution mechanisms are not fully determined. Herein, Ang-(1-7) stimulated migration of human and murine monocytes/macrophages in a MasR-, CCR2-, and MEK/ERK1/2–dependent manner. Pleural injection of Ang-(1-7) promoted nonphlogistic mononuclear cell influx alongside increased levels of CCL2, IL-10, and macrophage polarization toward a regulatory phenotype. Ang-(1-7) induction of CCL2 and mononuclear cell migration was also dependent on MasR and MEK/ERK. Of note, MasR was upregulated during the resolution phase of inflammation, and its pharmacological inhibition or genetic deficiency impaired mononuclear cell recruitment during self-resolving models of LPS pleurisy and E. coli peritonitis. Inhibition/absence of MasR was associated with reduced CCL2 levels, impaired phagocytosis of bacteria, efferocytosis, and delayed resolution of inflammation. In summary, we have uncovered a potentially novel proresolving feature of Ang-(1-7), namely the recruitment of mononuclear cells favoring efferocytosis, phagocytosis, and resolution of inflammation. Mechanistically, cell migration was dependent on MasR, CCR2, and the MEK/ERK pathway.
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Affiliation(s)
- Isabella Zaidan
- Departamento de Análises Clínicas e Toxicológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Luciana P Tavares
- Departamento Bioquimica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Michelle A Sugimoto
- Departamento Bioquimica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Kátia M Lima
- Departamento de Análises Clínicas e Toxicológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Graziele L Negreiros-Lima
- Departamento de Análises Clínicas e Toxicológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Lívia Cr Teixeira
- Departamento de Análises Clínicas e Toxicológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Thais C Miranda
- Departamento de Análises Clínicas e Toxicológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Bruno Vs Valiate
- Departamento Bioquimica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Allysson Cramer
- Departamento Bioquimica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Juliana Priscila Vago
- Departamento de Análises Clínicas e Toxicológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | | | - Jéssica Am Souza
- Departamento de Análises Clínicas e Toxicológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Laís C Grossi
- Departamento de Análises Clínicas e Toxicológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Vanessa Pinho
- Departamento Bioquimica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | | | - Robson A S Santos
- Departamento de Fisiologia e Farmacologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Mauro M Teixeira
- Departamento Bioquimica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Izabela Galvão
- Departamento Bioquimica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Lirlândia P Sousa
- Department of Clinical and Toxicological Analysis from the School of Pharma, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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Rajtik T, Galis P, Bartosova L, Paulis L, Goncalvesova E, Klimas J. Alternative RAS in Various Hypoxic Conditions: From Myocardial Infarction to COVID-19. Int J Mol Sci 2021; 22:ijms222312800. [PMID: 34884604 PMCID: PMC8657827 DOI: 10.3390/ijms222312800] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 11/20/2021] [Accepted: 11/24/2021] [Indexed: 12/28/2022] Open
Abstract
Alternative branches of the classical renin–angiotensin–aldosterone system (RAS) represent an important cascade in which angiotensin 2 (AngII) undergoes cleavage via the action of the angiotensin-converting enzyme 2 (ACE2) with subsequent production of Ang(1-7) and other related metabolites eliciting its effects via Mas receptor activation. Generally, this branch of the RAS system is described as its non-canonical alternative arm with counterbalancing actions to the classical RAS, conveying vasodilation, anti-inflammatory, anti-remodeling and anti-proliferative effects. The implication of this branch was proposed for many different diseases, ranging from acute cardiovascular conditions, through chronic respiratory diseases to cancer, nonetheless, hypoxia is one of the most prominent common factors discussed in conjugation with the changes in the activity of alternative RAS branches. The aim of this review is to bring complex insights into the mechanisms behind the various forms of hypoxic insults on the activity of alternative RAS branches based on the different duration of stimuli and causes (acute vs. intermittent vs. chronic), localization and tissue (heart vs. vessels vs. lungs) and clinical relevance of studied phenomenon (experimental vs. clinical condition). Moreover, we provide novel insights into the future strategies utilizing the alternative RAS as a diagnostic tool as well as a promising pharmacological target in serious hypoxia-associated cardiovascular and cardiopulmonary diseases.
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Affiliation(s)
- Tomas Rajtik
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, 832 32 Bratislava, Slovakia; (P.G.); (L.B.); (J.K.)
- Correspondence: ; Tel.: +42-12-501-17-391
| | - Peter Galis
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, 832 32 Bratislava, Slovakia; (P.G.); (L.B.); (J.K.)
| | - Linda Bartosova
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, 832 32 Bratislava, Slovakia; (P.G.); (L.B.); (J.K.)
| | - Ludovit Paulis
- Institute of Pathophysiology, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia;
| | - Eva Goncalvesova
- Department of Heart Failure, Clinic of Cardiology, National Institute of Cardiovascular Diseases, 831 01 Bratislava, Slovakia;
| | - Jan Klimas
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, 832 32 Bratislava, Slovakia; (P.G.); (L.B.); (J.K.)
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Barzegar M, Stokes KY, Chernyshev O, Kelley RE, Alexander JS. The Role of the ACE2/MasR Axis in Ischemic Stroke: New Insights for Therapy. Biomedicines 2021; 9:1667. [PMID: 34829896 PMCID: PMC8615891 DOI: 10.3390/biomedicines9111667] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 11/02/2021] [Accepted: 11/08/2021] [Indexed: 12/15/2022] Open
Abstract
Ischemic stroke remains the leading cause of neurologically based morbidity and mortality. Current stroke treatment is limited to two classes of FDA-approved drugs: thrombolytic agents (tissue plasminogen activator (tPA)) and antithrombotic agents (aspirin and heparin), which have a narrow time-window (<4.5 h) for administration after onset of stroke symptoms. While thrombolytic agents restore perfusion, they carry serious risks for hemorrhage, and do not influence damage responses during reperfusion. Consequently, stroke therapies that can suppress deleterious effects of ischemic injury are desperately needed. Angiotensin converting enzyme-2 (ACE2) has been recently suggested to beneficially influence experimental stroke outcomes by converting the vasoconstrictor Ang II into the vasodilator Ang 1-7. In this review, we extensively discuss the protective functions of ACE2-Ang (1-7)-MasR axis of renin angiotensin system (RAS) in ischemic stroke.
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Affiliation(s)
- Mansoureh Barzegar
- Molecular and Cellular Physiology, Ochsner-LSU Health Sciences Center, Shreveport, LA 71130-3932, USA; (M.B.); (K.Y.S.)
| | - Karen Y. Stokes
- Molecular and Cellular Physiology, Ochsner-LSU Health Sciences Center, Shreveport, LA 71130-3932, USA; (M.B.); (K.Y.S.)
| | - Oleg Chernyshev
- Neurology, Ochsner-LSU Health Sciences Center, Shreveport, LA 71130-3932, USA; (O.C.); (R.E.K.)
| | - Roger E. Kelley
- Neurology, Ochsner-LSU Health Sciences Center, Shreveport, LA 71130-3932, USA; (O.C.); (R.E.K.)
| | - Jonathan S. Alexander
- Molecular and Cellular Physiology, Ochsner-LSU Health Sciences Center, Shreveport, LA 71130-3932, USA; (M.B.); (K.Y.S.)
- Neurology, Ochsner-LSU Health Sciences Center, Shreveport, LA 71130-3932, USA; (O.C.); (R.E.K.)
- Medicine, LSU Health Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA
- Oral and Maxillofacial Surgery, Ochsner-LSU Health Sciences Center, Shreveport, LA 71130-3932, USA
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Collins KL, Younis US, Tanyaratsrisakul S, Polt R, Hay M, Mansour HM, Ledford JG. Angiotensin-(1-7) Peptide Hormone Reduces Inflammation and Pathogen Burden during Mycoplasma pneumoniae Infection in Mice. Pharmaceutics 2021; 13:1614. [PMID: 34683907 PMCID: PMC8539524 DOI: 10.3390/pharmaceutics13101614] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 09/30/2021] [Accepted: 10/01/2021] [Indexed: 12/15/2022] Open
Abstract
The peptide hormone, angiotensin (Ang-(1-7)), produces anti-inflammatory and protective effects by inhibiting production and expression of many cytokines and adhesion molecules that are associated with a cytokine storm. While Ang-(1-7) has been shown to reduce inflammation and airway hyperreactivity in models of asthma, little is known about the effects of Ang-(1-7) during live respiratory infections. Our studies were developed to test if Ang-(1-7) is protective in the lung against overzealous immune responses during an infection with Mycoplasma pneumonia (Mp), a common respiratory pathogen known to provoke exacerbations in asthma and COPD patients. Wild type mice were treated with infectious Mp and a subset of was given either Ang-(1-7) or peptide-free vehicle via oropharyngeal delivery within 2 h of infection. Markers of inflammation in the lung were assessed within 24 h for each set of animals. During Mycoplasma infection, one high dose of Ang-(1-7) delivered to the lungs reduced neutrophilia and Muc5ac, as well as Tnf-α and chemokines (Cxcl1) associated with acute respiratory distress syndrome (ARDS). Despite decreased inflammation, Ang-(1-7)-treated mice also had significantly lower Mp burden in their lung tissue, indicating decreased airway colonization. Ang-(1-7) also had an impact on RAW 264.7 cells, a commonly used macrophage cell line, by dose-dependently inhibiting TNF-α production while promoting Mp killing. These new findings provide additional support to the protective role(s) of Ang1-7 in controlling inflammation, which we found to be highly protective against live Mp-induced lung inflammation.
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Affiliation(s)
- Katie L. Collins
- Department of Immunobiology, College of Medicine, The University of Arizona, Tucson, AZ 85724, USA;
| | - Usir S. Younis
- Asthma and Airway Disease Research Center, Tucson, AZ 85724, USA; (U.S.Y.); (S.T.)
| | | | - Robin Polt
- Departments of Chemistry and Biochemistry, College of Science, The University of Arizona, Tucson, AZ 85721, USA;
| | - Meredith Hay
- Department of Physiology, College of Medicine, The University of Arizona, Tucson, AZ 85724, USA;
| | - Heidi M. Mansour
- BIO5 Institute, The University of Arizona, Tucson, AZ 85719, USA;
- Department of Medicine, Division of Translational & Regenerative Medicine, College of Medicine, The University of Arizona, Tucson, AZ 85724, USA
- Departments of Pharmacology/Toxicology and Pharmaceutical Sciences, College of Pharmacy, The University of Arizona, Tucson, AZ 85724, USA
| | - Julie G. Ledford
- Asthma and Airway Disease Research Center, Tucson, AZ 85724, USA; (U.S.Y.); (S.T.)
- BIO5 Institute, The University of Arizona, Tucson, AZ 85719, USA;
- Department of Cellular and Molecular Medicine, College of Medicine, The University of Arizona, Tucson, AZ 85721, USA
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Pathological AT1R-B2R Protein Aggregation and Preeclampsia. Cells 2021; 10:cells10102609. [PMID: 34685589 PMCID: PMC8533718 DOI: 10.3390/cells10102609] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 09/22/2021] [Accepted: 09/27/2021] [Indexed: 01/07/2023] Open
Abstract
Preeclampsia is one of the most frequent and severe complications of pregnancy. Symptoms of preeclampsia usually occur after 20 weeks of pregnancy and include hypertension and kidney dysfunction with proteinuria. Up to now, delivery of the infant has been the most effective and life-saving treatment to alleviate symptoms of preeclampsia because a causative treatment does not exist, which could prolong a pregnancy complicated with preeclampsia. Preeclampsia is a complex medical condition, which is attributed to a variety of different risk factors and causes. Risk factors account for insufficient placentation and impaired vasculogenesis and finally culminate in this life-threatening condition of pregnancy. Despite progress, many pathomechanisms and causes of preeclampsia are still incompletely understood. In recent years, it was found that excessive protein complex formation between G-protein-coupled receptors is a common sign of preeclampsia. Specifically, the aberrant heteromerization of two vasoactive G-protein-coupled receptors (GPCRs), the angiotensin II AT1 receptor and the bradykinin B2 receptor, is a causative factor of preeclampsia symptoms. Based on this knowledge, inhibition of abnormal GPCR protein complex formation is an experimental treatment approach of preeclampsia. This review summarizes the impact of pathological GPCR protein aggregation on symptoms of preeclampsia and delineates potential new therapeutic targets.
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Robust analysis of angiotensin peptides in human plasma: Column switching-parallel LC/ESI-SRM/MS without adsorption or enzymatic decomposition. Anal Biochem 2021; 630:114327. [PMID: 34364857 DOI: 10.1016/j.ab.2021.114327] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 07/30/2021] [Accepted: 08/02/2021] [Indexed: 11/20/2022]
Abstract
Angiotensin (Ang) peptides are the main effectors of the renin-angiotensin system (RAS) regulating diverse physiological conditions and are involved in renal and vascular diseases. Currently, quantitative analyses of Ang peptides in human plasma mainly rely on radioimmunoassay-based methods whose reported levels are quite divergent. Analyses are further complicated by the potential of Ang peptides to bind to solid surfaces, to be enzymatically decomposed during sample preparation, and to undergo post-translational modifications. A column switching-parallel LC/ESI-SRM/MS method has been developed for seven Ang peptides (Ang I, Ang II, Ang III, Ang IV, Ang 1-9, Ang 1-7, and Ang A) in human plasma. Aqueous acetonitrile (5%) containing 50 mM arginine (Arg) as a dissolving solution and a combination of protease inhibitors with formic acid were used to prevent adsorption and enzymatic degradation, respectively. Plasma samples were simply deproteinized with acetonitrile followed by clean-up with an on-line trap column via column-switching. Stable isotope dilution with [13C5,15N1-Val]-Ang peptides as internal standards was employed for quantitative analysis. The current methodology has been successfully applied to determine the plasma levels of Ang peptides in healthy participants, suggesting future applicability to studies of various diseases related to RAS.
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Khanna P, Soh HJ, Chen CH, Saxena R, Amin S, Naughton M, Joslin PN, Moore A, Bakouny Z, O'Callaghan C, Catalano P, Signoretti S, McKay R, Choueiri TK, Bhasin M, Walther T, Bhatt RS. ACE2 abrogates tumor resistance to VEGFR inhibitors suggesting angiotensin-(1-7) as a therapy for clear cell renal cell carcinoma. Sci Transl Med 2021; 13:13/577/eabc0170. [PMID: 33472951 DOI: 10.1126/scitranslmed.abc0170] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 09/24/2020] [Indexed: 12/24/2022]
Abstract
Angiotensin converting enzyme 2 (ACE2) is an enzyme that belongs to the renin-angiotensin system (RAS) and antagonizes the classical angiotensin (Ang) II/angiotensin II receptor type 1 (AT1) receptor pathway. Here, we report that higher ACE2 expression correlates with better overall survival in patients with clear cell renal cell carcinoma (ccRCC). Moreover, ACE2 has inhibitory effects on tumor proliferation in ccRCC in vitro and in preclinical animal models of ccRCC. We further show that Ang-(1-7), a heptapeptide generated by ACE2, is the likely mediator of this effect. Vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI) treatment of ccRCC xenografts decreased ACE2 expression, and combination treatment with VEGFR-TKI and Ang-(1-7) generated additive suppression of tumor growth and improved survival outcomes. Last, the addition of Ang-(1-7) to programmed death-ligand 1 (PD-L1) pathway inhibitor and VEGFR-TKI showed further growth suppression in an immunocompetent RCC model. Together, these results suggest that targeting the ACE2/Ang-(1-7) axis is a promising therapeutic strategy against ccRCC.
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Affiliation(s)
- Prateek Khanna
- Division of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.,Department of Medicine, Mount Auburn Hospital, Harvard Medical School, Cambridge, MA 02138, USA
| | - Hong Jie Soh
- Department of Pharmacology and Therapeutics, School of Medicine and School of Pharmacy, University College Cork, Cork T12 K8AF, Ireland
| | - Chun-Hau Chen
- Division of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Ruchi Saxena
- Division of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Seema Amin
- Division of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Maura Naughton
- Department of Pharmacology and Therapeutics, School of Medicine and School of Pharmacy, University College Cork, Cork T12 K8AF, Ireland
| | - Patrick Neset Joslin
- Division of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Andrew Moore
- Department of Pharmacology and Therapeutics, School of Medicine and School of Pharmacy, University College Cork, Cork T12 K8AF, Ireland
| | - Ziad Bakouny
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Carol O'Callaghan
- Department of Pharmacology and Therapeutics, School of Medicine and School of Pharmacy, University College Cork, Cork T12 K8AF, Ireland
| | - Paul Catalano
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Sabina Signoretti
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.,Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Rana McKay
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Toni K Choueiri
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Manoj Bhasin
- Division of Interdisciplinary Medicine and Biotechnology and Genomics, Proteomics, Bioinformatics and Systems Biology Center, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
| | - Thomas Walther
- Department of Pharmacology and Therapeutics, School of Medicine and School of Pharmacy, University College Cork, Cork T12 K8AF, Ireland. .,Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald 17489, Germany
| | - Rupal S Bhatt
- Division of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
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Rukavina Mikusic NL, Pineda AM, Gironacci MM. Angiotensin-(1-7) and Mas receptor in the brain. EXPLORATION OF MEDICINE 2021. [DOI: 10.37349/emed.2021.00046] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The renin-angiotensin system (RAS) is a key regulator of blood pressure and electrolyte homeostasis. Besides its importance as regulator of the cardiovascular function, the RAS has also been associated to the modulation of higher brain functions, including cognition, memory, depression and anxiety. For many years, angiotensin II (Ang II) has been considered the major bioactive component of the RAS. However, the existence of many other biologically active RAS components has currently been recognized, with similar, opposite, or distinct effects to those exerted by Ang II. Today, it is considered that the RAS is primarily constituted by two opposite arms. The pressor arm is composed by Ang II and the Ang II type 1 (AT1) receptor (AT1R), which mediates the vasoconstrictor, proliferative, hypertensive, oxidative and pro-inflammatory effects of the RAS. The depressor arm is mainly composed by Ang-(1-7), its Mas receptor (MasR) which mediates the depressor, vasodilatory, antiproliferative, antioxidant and anti-inflammatory effects of Ang-(1-7) and the AT2 receptor (AT2R), which opposes to the effects mediated by AT1R activation. Central Ang-(1-7) is implicated in the control of the cardiovascular function, thus participating in the regulation of blood pressure. Ang-(1-7) also exerts neuroprotective actions through MasR activation by opposing to the harmful effects of the Ang II/AT1R axis. This review is focused on the expression and regulation of the Ang-(1-7)/MasR axis in the brain, its main neuroprotective effects and the evidence regarding its involvement in the pathophysiology of several diseases at cardiovascular and neurological level.
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Affiliation(s)
- Natalia L. Rukavina Mikusic
- Dpto. Química Biológica, IQUIFIB (UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, 1113 Buenos Aires, Argentina
| | - Angélica M. Pineda
- Dpto. Química Biológica, IQUIFIB (UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, 1113 Buenos Aires, Argentina
| | - Mariela M. Gironacci
- Dpto. Química Biológica, IQUIFIB (UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, 1113 Buenos Aires, Argentina
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Behl T, Shah S, Kaur I, Yadav S, Kanwar R, Seth S, Wig N, Sharma KK, Yadav HN. Role of ACE 2 and Vitamin D: The Two Players in Global Fight against COVID-19 Pandemic. ANNALS OF THE NATIONAL ACADEMY OF MEDICAL SCIENCES (INDIA) 2021. [DOI: 10.1055/s-0041-1729781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
AbstractThe global pandemic of coronavirus disease 2019 (COVID-19) has spread across the borders, gaining attention from both health care professional and researchers to understand the mode of entry and actions induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), its causative agent in the human body. The role of angiotensin-converting enzyme–2 (ACE2) in facilitating the entry of the virus in the host cell by binding to it is similar to SARS-CoV-1, the causative agent for severe acute respiratory syndrome (SARS) which emerged in 2003. Besides the role of ACE2 as a molecular target for the virus, the review displays the potential benefits of ACE2 enzyme and various agents that modify its activity in curbing the effects of the deadly virus, thus unfolding a dual character of ACE2 in the current pandemic. As evident by the differences in the susceptibility toward viral infection in children and geriatric population, it must be noted that the older population has limited ACE2 levels and greater infection risk, whereas the situation is reversed in the case of the pediatric population, demonstrating the defensive character of ACE2 in the latter, despite acting as receptor target for SARS-CoV-2. Also, the upregulation of ACE2 levels by estrogen has indicated greater resistance to infection in females than in the male human population. ACE2 is a carboxypeptidase, which degrades angiotensin II and counteracts its actions to protect against cardiovascular risks associated with the virus. Another contribution of this enzyme is supported by the role of circulating soluble ACE2, which acts as a receptor to bind the virus but does not mediate its actions, therefore blocking its interaction to membrane-bound ACE2 receptors. The review also shares the enhanced risks of developing COVID-19 infection by using ACE inhibitors and ARBs. However, both these agents have been reported to upregulate ACE2 levels; yet, adequate evidence regarding their role is quite inconsistent in human studies. Furthermore, the role of vitamin D has been highlighted in regulating the immune system of the body through renin-angiotensin-aldosterone system (RAAS) inhibition, by downregulating host cell receptor expression to prevent virus attachment. Besides, vitamin D also acts through several other mechanisms like upregulating antimicrobial peptides, fighting against the proinflammatory milieu created by the invading virus, and interfering with the viral replication cycle as well as calcitriol-mediated blockage of CREB protein. Hypovitaminosis D is attributed to elevated risks of acute respiratory distress syndrome (ARDS), lung damage, and cardiovascular disorders, further increasing the severity of COVID-19 infection.
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Affiliation(s)
- Tapan Behl
- Department of Pharmacology, Chitkara University, Punjab, India
| | - Sadia Shah
- Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India
| | - Ishnoor Kaur
- Department of Pharmacology, Chitkara University, Punjab, India
| | - Sushma Yadav
- Department of Obstetrics and Gynaecology, Shaheed Hasan Khan Mewati Government Medical College, Haryana, India
| | - Raj Kanwar
- Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India
| | - Sandeep Seth
- Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India
| | - Naveet Wig
- Department of Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - K. K. Sharma
- National Academy of Medical Sciences (India), New Delhi, India
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Yamagata R, Nemoto W, Fujita M, Nakagawasai O, Tan-No K. Angiotensin (1-7) Attenuates the Nociceptive Behavior Induced by Substance P and NMDA via Spinal MAS1. Biol Pharm Bull 2021; 44:742-746. [PMID: 33952831 DOI: 10.1248/bpb.b20-01004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The intrathecal (i.t.) injection of substance P (SP) and N-methyl-D-aspartate (NMDA) induce transient nociceptive response by activating neurokinin (NK) 1 and NMDA receptors, respectively. We have recently reported that angiotensin (Ang) (1-7), an N-terminal fragment of Ang II, could alleviate several types of pain including neuropathic and inflammatory pain by activating spinal MAS1. Here, we investigated whether Ang (1-7) can inhibit the SP- and NMDA-induced nociceptive response. The nociceptive response induced by an i.t. injection of SP or NMDA was assessed by measuring the duration of hindlimb scratching directed toward the flank, biting and/or licking of the hindpaw or the tail for 5 min. Localization of MAS1 and either NK1 or NMDA receptors in the lumbar superficial dorsal horn was determined by immunohistochemical observation. The nociceptive response induced by SP and NMDA was attenuated by the i.t. co-administration of Ang (1-7) (0.03-3 pmol) in a dose-dependent manner. The inhibitory effects of Ang (1-7) (3 pmol) were attenuated by A779 (100 pmol), a MAS1 antagonist. Moreover, immunohistochemical analysis showed that spinal MAS1 co-localized with NK1 receptors and NMDA receptors on cells in the dorsal horn. Taken together, the i.t. injection of Ang (1-7) attenuated the nociceptive response induced by SP and NMDA via spinal MAS1, which co-localized with NK1 and NMDA receptors. Thus, the spinal Ang (1-7)/MAS1 pathway could represent a therapeutic target to effectively attenuate spinal pain transmission caused by the activation of NK1 or NMDA receptors.
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Affiliation(s)
- Ryota Yamagata
- Division of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University
| | - Wataru Nemoto
- Division of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University
| | - Maho Fujita
- Division of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University
| | - Osamu Nakagawasai
- Division of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University
| | - Koichi Tan-No
- Division of Pharmacology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University
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Khajehpour S, Aghazadeh-Habashi A. Targeting the Protective Arm of the Renin-Angiotensin System: Focused on Angiotensin-(1-7). J Pharmacol Exp Ther 2021; 377:64-74. [PMID: 33495248 DOI: 10.1124/jpet.120.000397] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 01/19/2021] [Indexed: 11/22/2022] Open
Abstract
The in vivo application and efficacy of many therapeutic peptides is limited because of their instability and proteolytic degradation. Novel strategies for developing therapeutic peptides with higher stability toward proteolytic degradation would be extremely valuable. Such approaches could improve systemic bioavailability and enhance therapeutic effects. The renin-angiotensin system (RAS) is a hormonal system within the body essential for the regulation of blood pressure and fluid balance. The RAS is composed of two opposing classic and protective arms. The balance between these two arms is critical for the homeostasis of the body's physiologic function. Activation of the RAS results in the suppression of its protective arm, which has been reported in inflammatory and pathologic conditions such as arthritis, cardiovascular diseases, diabetes, and cancer. Clinical application of angiotensin-(1-7) [Ang-(1-7)], a RAS critical regulatory peptide, augments the protective arm and restores balance hampered by its enzymatic and chemical instability. Several attempts to increase the half-life and efficacy of this heptapeptide using more stable analogs and different drug delivery approaches have been made. This review article provides an overview of efforts targeting the RAS protective arm. It provides a critical analysis of Ang-(1-7) or its homologs' novel drug delivery systems using different administration routes, their pharmacological characterization, and therapeutic potential in various clinical settings. SIGNIFICANCE STATEMENT: Ang-(1-7) is a unique peptide component of the renin-angiotensin system with vast potential for clinical applications that modulate various inflammatory diseases. Novel Ang-(1-7) peptide drug delivery could compensate its lack of stability for effective clinical application.
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Affiliation(s)
- Sana Khajehpour
- Department of Biomedical and Pharmaceutical Sciences, Idaho State University, Pocatello, ID
| | - Ali Aghazadeh-Habashi
- Department of Biomedical and Pharmaceutical Sciences, Idaho State University, Pocatello, ID
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Senger N, C Parletta A, Marques BVD, Akamine EH, Diniz GP, Campagnole-Santos MJ, Santos RAS, Barreto-Chaves MLM. Angiotensin-(1-7) prevents T3-induced cardiomyocyte hypertrophy by upregulating FOXO3/SOD1/catalase and downregulating NF-ĸB. J Cell Physiol 2021; 236:3059-3072. [PMID: 32964425 DOI: 10.1002/jcp.30069] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 09/08/2020] [Accepted: 09/11/2020] [Indexed: 11/05/2022]
Abstract
Clinical studies have shown a correlation between thyroid disorders and cardiac diseases. High levels of triiodothyronine (T3) induce cardiac hypertrophy, a risk factor for cardiac complications and heart failure. Previous results have demonstrated that angiotensin-(1-7) is able to block T3-induced cardiac hypertrophy; however, the molecular mechanisms involved in this event have not been fully elucidated. Here, we evidenced the contribution of FOXO3 signaling to angiotensin-(1-7) effects. Angiotensin-(1-7) treatment increased nuclear FOXO3 levels and reduced p-FOXO3 levels (inactive form) in isolated cardiomyocytes. Knockdown of FOXO3 by RNA silencing abrogated the antihypertrophic effect of angiotensin-(1-7). Increased expression of antioxidant enzymes superoxide dismutase 1 (SOD1 and catalase) and lower levels of reactive oxygen species and nuclear factor-κB (NF-κB) were observed after angiotensin-(1-7) treatment in vitro. Consistent with these results, transgenic rats overexpressing angiotensin-(1-7) displayed increased nuclear FOXO3 and SOD1 levels and reduced NF-κB levels in the heart. These results provide a new molecular mechanism responsible for the antihypertrophic effect of angiotensin-(1-7), which may contribute to future therapeutic targets.
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Affiliation(s)
- Nathalia Senger
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
| | - Aline C Parletta
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
| | - Bruno V D Marques
- Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
| | - Eliana H Akamine
- Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
| | - Gabriela P Diniz
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
| | - Maria J Campagnole-Santos
- Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Robson A S Santos
- Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
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