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Akhtar S, Babiker F, Al-Kouh A, F Benter I. The cardiac toxicity of PAMAM dendrimer drug delivery systems can be attenuated with the adjunct use of cardioprotective agents. BIOMOLECULES & BIOMEDICINE 2025; 25:914-924. [PMID: 39319862 PMCID: PMC11959388 DOI: 10.17305/bb.2024.10735] [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: 05/13/2024] [Revised: 08/18/2024] [Accepted: 08/18/2024] [Indexed: 09/26/2024]
Abstract
Polyamidoamine (PAMAM) dendrimer nanoparticles are efficient drug delivery vectors with potential clinical applications in nanomedicine. However, PAMAMs can compromise heart function, and strategies to mitigate cardiotoxicity would be beneficial. In this study, we investigated whether the adjunct use of three key cardioprotective agents could prevent cardiac injury induced by a seventh-generation cationic PAMAM dendrimer (G7). Isolated rat hearts were subjected to ischemia and reperfusion (I/R) injury in the presence or absence of G7 or the cardioprotective agents Losartan, epidermal growth factor (EGF), or S-nitroso-N-acetylpenicillamine (SNAP). I/R injury significantly compromised cardiac function, in terms of left ventricular (LV) hemodynamics, contractility, and vascular dynamics, which were markedly improved (P < 0.05) by the administration of Losartan, EGF, or SNAP alone, confirming their cardioprotective effects. The administration of G7 significantly worsened cardiac function recovery following I/R (P < 0.05). G7-induced impairments in cardiac and vascular dynamics were significantly improved by co-administration of Losartan, EGF, or SNAP. Treatment with G7 also significantly increased cardiac enzyme levels and infarct size, both of which were markedly reduced upon co-infusion of Losartan, EGF, or SNAP (P < 0.05). Thus, G7 deteriorates the recovery of cardiac function in isolated hearts subjected to I/R injury, which can be rescued by co-administration of Losartan, EGF, or SNAP. These findings enhance our understanding of PAMAM dendrimer nanotoxicology in the mammalian heart and suggest that the adjunct use of cardioprotective agents is an effective strategy for mitigating the cardiotoxicity of these dendrimers and potentially other drug delivery systems.
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Affiliation(s)
- Saghir Akhtar
- College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Fawzi Babiker
- Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Aisha Al-Kouh
- Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Ibrahim F Benter
- Faculty of Pharmacy, Final International University, Kyrenia, North Cyprus
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Stevens SA, Sunilkumar S, Subrahmanian SM, Toro AL, Cavus O, Omorogbe EV, Bradley EA, Dennis MD. REDD1 Deletion Suppresses NF-κB Signaling in Cardiomyocytes and Prevents Deficits in Cardiac Function in Diabetic Mice. Int J Mol Sci 2024; 25:6461. [PMID: 38928166 PMCID: PMC11204184 DOI: 10.3390/ijms25126461] [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: 05/17/2024] [Revised: 06/06/2024] [Accepted: 06/08/2024] [Indexed: 06/28/2024] Open
Abstract
Activation of the transcription factor NF-κB in cardiomyocytes has been implicated in the development of cardiac function deficits caused by diabetes. NF-κB controls the expression of an array of pro-inflammatory cytokines and chemokines. We recently discovered that the stress response protein regulated in development and DNA damage response 1 (REDD1) was required for increased pro-inflammatory cytokine expression in the hearts of diabetic mice. The studies herein were designed to extend the prior report by investigating the role of REDD1 in NF-κB signaling in cardiomyocytes. REDD1 genetic deletion suppressed NF-κB signaling and nuclear localization of the transcription factor in human AC16 cardiomyocyte cultures exposed to TNFα or hyperglycemic conditions. A similar suppressive effect on NF-κB activation and pro-inflammatory cytokine expression was also seen in cardiomyocytes by knocking down the expression of GSK3β. NF-κB activity was restored in REDD1-deficient cardiomyocytes exposed to hyperglycemic conditions by expression of a constitutively active GSK3β variant. In the hearts of diabetic mice, REDD1 was required for reduced inhibitory phosphorylation of GSK3β at S9 and upregulation of IL-1β and CCL2. Diabetic REDD1+/+ mice developed systolic functional deficits evidenced by reduced ejection fraction. By contrast, REDD1-/- mice did not exhibit a diabetes-induced deficit in ejection fraction and left ventricular chamber dilatation was reduced in diabetic REDD1-/- mice, as compared to diabetic REDD1+/+ mice. Overall, the results support a role for REDD1 in promoting GSK3β-dependent NF-κB signaling in cardiomyocytes and in the development of cardiac function deficits in diabetic mice.
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Affiliation(s)
- Shaunaci A. Stevens
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Siddharth Sunilkumar
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Sandeep M. Subrahmanian
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Allyson L. Toro
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Omer Cavus
- Division of Cardiovascular Medicine, Penn State Health Heart and Vascular Institute, Hershey S. Milton Medical Center, Hershey, PA 17033, USA
| | - Efosa V. Omorogbe
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA
| | - Elisa A. Bradley
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA
- Division of Cardiovascular Medicine, Penn State Health Heart and Vascular Institute, Hershey S. Milton Medical Center, Hershey, PA 17033, USA
| | - Michael D. Dennis
- Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA
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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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Hu W, Tan J, Lin Y, Tao Y, Zhou Q. Bibliometric and visual analysis of ACE2/Ang 1-7/MasR axis in diabetes and its microvascular complications from 2000 to 2023. Heliyon 2024; 10:e31405. [PMID: 38807880 PMCID: PMC11130665 DOI: 10.1016/j.heliyon.2024.e31405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 05/15/2024] [Accepted: 05/15/2024] [Indexed: 05/30/2024] Open
Abstract
Background The pathogenesis of diabetes and its microvascular complications are intimately associated with renin angiotensin system dysregulation. Evidence suggests the angiotensin converting enzyme 2 (ACE2)/angiotensin 1-7 (Ang 1-7)/Mas receptor (MasR) axis regulates metabolic imbalances, inflammatory responses, reduces oxidative stress, and sustains microvascular integrity, thereby strengthening defences against diabetic conditions. This study aims to conduct a comprehensive analysis of the ACE2/Ang 1-7/MasR axis in diabetes and its microvascular complications over the past two decades, focusing on key contributors, research hotspots, and thematic trends. Methods This cross-sectional bibliometric analysis of 349 English-language publications was performed using HistCite, VOSviewer, CiteSpace, and Bibliometrix R for visualization and metric analysis. Primary analytical metrics included publication count and keyword trend dynamics. Results The United States, contributing 105 articles, emerged as the most productive country, with the University of Florida leading institutions with 18 publications. Benter IF was the most prolific author with 14 publications, and Clinical Science was the leading journal with 13 articles. A total of 151 of the 527 author's keywords with two or more occurrences clustered into four major clusters: diabetic microvascular pathogenesis, metabolic systems, type 2 diabetes, and coronavirus infections. Keywords such as "SARS", "ACE2", "coronavirus", "receptor" and "infection" displayed the strongest citation bursts. The thematic evolution in this field expanded from focusing on the renin angiotensin system (2002-2009) to incorporating ACE2 and diabetes metabolism (2010-2016). The latter period (2017-2023) witnessed a significant surge in diabetes research, reflecting the impact of COVID-19 and associated conditions such as diabetic retinopathy and cardiomyopathy. Conclusions This scientometric study offers a detailed analysis of the ACE2/Ang 1-7/MasR axis in diabetes and its microvascular complications, providing valuable insights for future research directions.
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Affiliation(s)
- Weiwen Hu
- Department of Ophthalmology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi Province, People's Republic of China
| | - Jian Tan
- Department of Ophthalmology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi Province, People's Republic of China
| | - Yeting Lin
- Department of Ophthalmology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi Province, People's Republic of China
| | - Yulin Tao
- Department of Ophthalmology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi Province, People's Republic of China
| | - Qiong Zhou
- Department of Ophthalmology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi Province, People's Republic of China
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Akhtar S, Babiker F, Akhtar UA, Benter IF. Mitigating Cardiotoxicity of Dendrimers: Angiotensin-(1-7) via Its Mas Receptor Ameliorates PAMAM-Induced Cardiac Dysfunction in the Isolated Mammalian Heart. Pharmaceutics 2022; 14:pharmaceutics14122673. [PMID: 36559167 PMCID: PMC9781033 DOI: 10.3390/pharmaceutics14122673] [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: 10/28/2022] [Revised: 11/25/2022] [Accepted: 11/27/2022] [Indexed: 12/02/2022] Open
Abstract
AIM The influence of the physiochemical properties of dendrimer nanoparticles on cardiac contractility and hemodynamics are not known. Herein, we investigated (a) the effect of polyamidoamine (PAMAM) dendrimer generation (G7, G6, G5, G4 and G3) and surface chemistry (-NH2, -COOH and -OH) on cardiac function in mammalian hearts following ischemia-reperfusion (I/R) injury, and (b) determined if any PAMAM-induced cardiotoxicity could be mitigated by Angiotensin-(1-7) (Ang-(1-7), a cardioprotective agent. METHODS Hearts isolated from male Wistar rats underwent regional I/R and/or treatment with different PAMAM dendrimers, Ang-(1-7) or its MAS receptors antagonists. Thirty minutes of regional ischemia through ligation of the left anterior descending coronary artery was followed by 30 min of reperfusion. All treatments were initiated 5 min prior to reperfusion and maintained during the first 10 min of reperfusion. Cardiac function parameters for left ventricular contractility, hemodynamics and vascular dynamics data were acquired digitally, whereas cardiac enzymes and infarct size were used as measures of cardiac injury. RESULTS Treatment of isolated hearts with increasing doses of G7 PAMAM dendrimer progressively exacerbated recovery of cardiac contractility and hemodynamic parameters post-I/R injury. Impairment of cardiac function was progressively less on decreasing dendrimer generation with G3 exhibiting little or no cardiotoxicity. Cationic PAMAMs (-NH2) were more toxic than anionic (-COOH), with neutral PAMAMs (-OH) exhibiting the least cardiotoxicity. Cationic G7 PAMAM-induced cardiac dysfunction was significantly reversed by Ang-(1-7) administration. These cardioprotective effects of Ang-(1-7) were significantly revoked by administration of the MAS receptor antagonists, A779 and D-Pro7-Ang-(1-7). CONCLUSIONS PAMAM dendrimers can impair the recovery of hearts from I/R injury in a dose-, dendrimer-generation-(size) and surface-charge dependent manner. Importantly, PAMAM-induced cardiotoxicity could be mitigated by Ang-(1-7) acting through its MAS receptor. Thus, this study highlights the activation of Ang-(1-7)/Mas receptor axis as a novel strategy to overcome dendrimer-induced cardiotoxicity.
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Affiliation(s)
- Saghir Akhtar
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar
- Correspondence: (S.A.); (F.B.)
| | - Fawzi Babiker
- Departments of Physiology, Faculty of Medicine, Health Science Center, Kuwait University, Safat P.O. Box 24923, Kuwait
- Correspondence: (S.A.); (F.B.)
| | - Usman A. Akhtar
- Department of Mechanical and Chemical Engineering, College of Engineering, Qatar University, Doha P.O. Box 2713, Qatar
| | - Ibrahim F. Benter
- Faculty of Medicine, Eastern Mediterranean University, Famagusta 99628, North Cyprus, Turkey
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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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El-Azab MF, Wakiel AE, Nafea YK, Youssef ME. Role of cannabinoids and the endocannabinoid system in modulation of diabetic cardiomyopathy. World J Diabetes 2022; 13:387-407. [PMID: 35664549 PMCID: PMC9134026 DOI: 10.4239/wjd.v13.i5.387] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/18/2021] [Accepted: 04/28/2022] [Indexed: 02/06/2023] Open
Abstract
Diabetic complications, chiefly seen in long-term situations, are persistently deleterious to a large extent, requiring multi-factorial risk reduction strategies beyond glycemic control. Diabetic cardiomyopathy is one of the most common deleterious diabetic complications, being the leading cause of mortality among diabetic patients. The mechanisms of diabetic cardiomyopathy are multi-factorial, involving increased oxidative stress, accumulation of advanced glycation end products (AGEs), activation of various pro-inflammatory and cell death signaling pathways, and changes in the composition of extracellular matrix with enhanced cardiac fibrosis. The novel lipid signaling system, the endocannabinoid system, has been implicated in the pathogenesis of diabetes and its complications through its two main receptors: Cannabinoid receptor type 1 and cannabinoid receptor type 2, alongside other components. However, the role of the endocannabinoid system in diabetic cardiomyopathy has not been fully investigated. This review aims to elucidate the possible mechanisms through which cannabinoids and the endocannabinoid system could interact with the pathogenesis and the development of diabetic cardiomyopathy. These mechanisms include oxidative/ nitrative stress, inflammation, accumulation of AGEs, cardiac remodeling, and autophagy. A better understanding of the role of cannabinoids and the endocannabinoid system in diabetic cardiomyopathy may provide novel strategies to manipulate such a serious diabetic complication.
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Affiliation(s)
- Mona F El-Azab
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Ahmed E Wakiel
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Yossef K Nafea
- Program of Biochemistry, McMaster University, Hamilton L8S 4L8, Ontario, Canada
| | - Mahmoud E Youssef
- Department of Pharmacology and Biochemistry, Delta University for Science and Technology, Mansoura 35511, New Cairo, Egypt
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Echeverría-Rodríguez O, Godínez-Chaparro B, Gómez-García MV, Mata-Bermúdez A, Del Valle-Mondragón L, Gallardo-Ortíz IA, Villalobos-Molina R. Participation of angiotensin-(1-7) in exercise-induced analgesia in rats with neuropathic pain. Peptides 2021; 146:170670. [PMID: 34634392 DOI: 10.1016/j.peptides.2021.170670] [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: 07/02/2021] [Revised: 09/21/2021] [Accepted: 10/02/2021] [Indexed: 11/29/2022]
Abstract
Exercise reduces neuropathic pain in animals and humans. Recent studies indicate that training exercise favors the synthesis and action of angiotensin-(1-7) (Ang-(1-7)), a vasoactive peptide of the renin-angiotensin system (RAS), in various tissues. Interestingly, Ang-(1-7) also relieves neuropathic pain; however, it remains to be elucidated whether exercise mitigates this type of pain through Ang-(1-7). In this study, we investigated the role of Ang-(1-7) in exercise-induced analgesia in a neuropathic pain model. Male Wistar rats were ligated of lumbar spinal nerves (L5 and L6) or sham-operated. Then, they were subjected to acute (2-h) or chronic (4-week) exercise protocols. Tactile allodynia was evaluated before and after each exercise intervention. Microosmotic pumps were implanted subcutaneously for the release of Ang-(1-7) or A779 (selective Mas receptor (MasR; Ang-(1-7) receptor) antagonist). Plasma levels of Ang II and Ang-(1-7) were quantified by HPLC. Spinal nerve ligation (SNL) produced tactile allodynia. Both acute and chronic exercise reversed this neuropathic behavior. A779 treatment prevented the antiallodynic effect induced by each exercise protocol. SNL increased the plasma Ang II/Ang-(1-7) ratio; however, exercise did not modify it. Acute treatment with Ang-(1-7) via MasR mimicked exercise-mediated antinociception. Collectively, these results suggest that activation of the Ang-(1-7)/MasR axis of the RAS represents a potential novel mechanism by which exercise attenuates neuropathic pain in rats.
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Affiliation(s)
- Omar Echeverría-Rodríguez
- Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Coyoacán, Ciudad de México, Mexico; Departamento de Sistemas Biológicos, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Unidad Xochimilco, Coyoacán, Ciudad de México, Mexico.
| | - Beatriz Godínez-Chaparro
- Departamento de Sistemas Biológicos, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Unidad Xochimilco, Coyoacán, Ciudad de México, Mexico
| | - María V Gómez-García
- Departamento de Sistemas Biológicos, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Unidad Xochimilco, Coyoacán, Ciudad de México, Mexico
| | - Alfonso Mata-Bermúdez
- Departamento de Sistemas Biológicos, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Unidad Xochimilco, Coyoacán, Ciudad de México, Mexico
| | - Leonardo Del Valle-Mondragón
- Departamento de Farmacología, Instituto Nacional de Cardiología "Ignacio Chávez", Tlalpan, Ciudad de México, Mexico
| | - Itzell A Gallardo-Ortíz
- Unidad de Investigación en Biomedicina y Carrera de Enfermería, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, Mexico
| | - Rafael Villalobos-Molina
- Unidad de Investigación en Biomedicina y Carrera de Enfermería, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, Mexico
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9
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Shraim BA, Moursi MO, Benter IF, Habib AM, Akhtar S. The Role of Epidermal Growth Factor Receptor Family of Receptor Tyrosine Kinases in Mediating Diabetes-Induced Cardiovascular Complications. Front Pharmacol 2021; 12:701390. [PMID: 34408653 PMCID: PMC8365470 DOI: 10.3389/fphar.2021.701390] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 07/14/2021] [Indexed: 12/15/2022] Open
Abstract
Diabetes mellitus is a major debilitating disease whose global incidence is progressively increasing with currently over 463 million adult sufferers and this figure will likely reach over 700 million by the year 2045. It is the complications of diabetes such as cardiovascular, renal, neuronal and ocular dysfunction that lead to increased patient morbidity and mortality. Of these, cardiovascular complications that can result in stroke and cardiomyopathies are 2- to 5-fold more likely in diabetes but the underlying mechanisms involved in their development are not fully understood. Emerging research suggests that members of the Epidermal Growth Factor Receptor (EGFR/ErbB/HER) family of tyrosine kinases can have a dual role in that they are beneficially required for normal development and physiological functioning of the cardiovascular system (CVS) as well as in salvage pathways following acute cardiac ischemia/reperfusion injury but their chronic dysregulation may also be intricately involved in mediating diabetes-induced cardiovascular pathologies. Here we review the evidence for EGFR/ErbB/HER receptors in mediating these dual roles in the CVS and also discuss their potential interplay with the Renin-Angiotensin-Aldosterone System heptapeptide, Angiotensin-(1-7), as well the arachidonic acid metabolite, 20-HETE (20-hydroxy-5, 8, 11, 14-eicosatetraenoic acid). A greater understanding of the multi-faceted roles of EGFR/ErbB/HER family of tyrosine kinases and their interplay with other key modulators of cardiovascular function could facilitate the development of novel therapeutic strategies for treating diabetes-induced cardiovascular complications.
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Affiliation(s)
- Bara A Shraim
- College of Medicine, QU Health, Qatar University, Doha, Qatar.,Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar
| | - Moaz O Moursi
- College of Medicine, QU Health, Qatar University, Doha, Qatar.,Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar
| | - Ibrahim F Benter
- Faculty of Medicine, Eastern Mediterranean University, Famagusta, North Cyprus
| | - Abdella M Habib
- College of Medicine, QU Health, Qatar University, Doha, Qatar.,Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar
| | - Saghir Akhtar
- College of Medicine, QU Health, Qatar University, Doha, Qatar.,Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar
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10
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Laghlam D, Jozwiak M, Nguyen LS. Renin-Angiotensin-Aldosterone System and Immunomodulation: A State-of-the-Art Review. Cells 2021; 10:cells10071767. [PMID: 34359936 PMCID: PMC8303450 DOI: 10.3390/cells10071767] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 06/30/2021] [Accepted: 07/09/2021] [Indexed: 12/11/2022] Open
Abstract
The renin–angiotensin system (RAS) has long been described in the field of cardiovascular physiology as the main player in blood pressure homeostasis. However, other effects have since been described, and include proliferation, fibrosis, and inflammation. To illustrate the immunomodulatory properties of the RAS, we chose three distinct fields in which RAS may play a critical role and be the subject of specific treatments. In oncology, RAS hyperactivation has been associated with tumor migration, survival, cell proliferation, and angiogenesis; preliminary data showed promise of the benefit of RAS blockers in patients treated for certain types of cancer. In intensive care medicine, vasoplegic shock has been associated with severe macro- and microcirculatory imbalance. A relative insufficiency in angiotensin II (AngII) was associated to lethal outcomes and synthetic AngII has been suggested as a specific treatment in these cases. Finally, in solid organ transplantation, both AngI and AngII have been associated with increased rejection events, with a regional specificity in the RAS activity. These elements emphasize the complexity of the direct and indirect interactions of RAS with immunomodulatory pathways and warrant further research in the field.
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11
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Gonzalez SM, Siddik AB, Su RC. Regulated Intramembrane Proteolysis of ACE2: A Potential Mechanism Contributing to COVID-19 Pathogenesis? Front Immunol 2021; 12:612807. [PMID: 34163462 PMCID: PMC8215698 DOI: 10.3389/fimmu.2021.612807] [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: 09/30/2020] [Accepted: 05/07/2021] [Indexed: 12/22/2022] Open
Abstract
Since being identified as a key receptor for SARS-CoV-2, Angiotensin converting enzyme 2 (ACE2) has been studied as one of the potential targets for the development of preventative and/or treatment options. Tissue expression of ACE2 and the amino acids interacting with the spike protein of SARS-CoV-2 have been mapped. Furthermore, the recombinant soluble extracellular domain of ACE2 is already in phase 2 trials as a treatment for SARS-CoV-2 infection. Most studies have continued to focus on the ACE2 extracellular domain, which is known to play key roles in the renin angiotensin system and in amino acid uptake. However, few also found ACE2 to have an immune-modulatory function and its intracellular tail may be one of the signaling molecules in regulating cellular activation. The implication of its immune-modulatory role in preventing the cytokine-storm, observed in severe COVID-19 disease outcomes requires further investigation. This review focuses on the regulated proteolytic cleavage of ACE2 upon binding to inducer(s), such as the spike protein of SARS-CoV, the potential of cleaved ACE2 intracellular subdomain in regulating cellular function, and the ACE2's immune-modulatory function. This knowledge is critical for targeting ACE2 levels for developing prophylactic treatment or preventative measures in SARS-CoV infections.
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Affiliation(s)
- Sandra M. Gonzalez
- Department of Medical Microbiology and Infectious Diseases, University of Manitobag, Winnipe, MB, Canada
| | - Abu Bakar Siddik
- Department of Medical Microbiology and Infectious Diseases, University of Manitobag, Winnipe, MB, Canada
- National HIV and Retrovirology Laboratories, J.C. Wilt Infectious Diseases Research Centre, National Microbiology Laboratories, Public Health Agency of Canada, Winnipeg, MB, Canada
| | - Ruey-Chyi Su
- Department of Medical Microbiology and Infectious Diseases, University of Manitobag, Winnipe, MB, Canada
- National HIV and Retrovirology Laboratories, J.C. Wilt Infectious Diseases Research Centre, National Microbiology Laboratories, Public Health Agency of Canada, Winnipeg, MB, Canada
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12
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ACE2 in the renin-angiotensin system. Clin Sci (Lond) 2020; 134:3063-3078. [PMID: 33264412 DOI: 10.1042/cs20200478] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 11/12/2020] [Accepted: 11/19/2020] [Indexed: 01/01/2023]
Abstract
In 2020 we are celebrating the 20th anniversary of the angiotensin-converting enzyme 2 (ACE2) discovery. This event was a landmark that shaped the way that we see the renin-angiotensin system (RAS) today. ACE2 is an important molecular hub that connects the RAS classical arm, formed mainly by the octapeptide angiotensin II (Ang II) and its receptor AT1, with the RAS alternative or protective arm, formed mainly by the heptapeptides Ang-(1-7) and alamandine, and their receptors, Mas and MrgD, respectively. In this work we reviewed classical and modern literature to describe how ACE2 is a critical component of the protective arm, particularly in the context of the cardiac function, coagulation homeostasis and immune system. We also review recent literature to present a critical view of the role of ACE2 and RAS in the SARS-CoV-2 pandemic.
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13
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Mahmudpour M, Roozbeh J, Keshavarz M, Farrokhi S, Nabipour I. COVID-19 cytokine storm: The anger of inflammation. Cytokine 2020; 133:155151. [PMID: 32544563 PMCID: PMC7260598 DOI: 10.1016/j.cyto.2020.155151] [Citation(s) in RCA: 320] [Impact Index Per Article: 64.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 05/20/2020] [Accepted: 05/28/2020] [Indexed: 02/06/2023]
Abstract
Patients with COVID-19 who require ICU admission might have the cytokine storm. It is a state of out-of-control release of a variety of inflammatory cytokines. The molecular mechanism of the cytokine storm has not been explored extensively yet. The attachment of SARS-CoV-2 spike glycoprotein with angiotensin-converting enzyme 2 (ACE2), as its cellular receptor, triggers complex molecular events that leads to hyperinflammation. Four molecular axes that may be involved in SARS-CoV-2 driven inflammatory cytokine overproduction are addressed in this work. The virus-mediated down-regulation of ACE2 causes a burst of inflammatory cytokine release through dysregulation of the renin-angiotensin-aldosterone system (ACE/angiotensin II/AT1R axis), attenuation of Mas receptor (ACE2/MasR axis), increased activation of [des-Arg9]-bradykinin (ACE2/bradykinin B1R/DABK axis), and activation of the complement system including C5a and C5b-9 components. The molecular clarification of these axes will elucidate an array of therapeutic strategies to confront the cytokine storm in order to prevent and treat COVID-19 associated acute respiratory distress syndrome.
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Affiliation(s)
- Mehdi Mahmudpour
- The Persian Gulf Tropical Medicine Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Jamshid Roozbeh
- Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohsen Keshavarz
- The Persian Gulf Tropical Medicine Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Shokrollah Farrokhi
- Department of Immunology and Allergy, The Persian Gulf Tropical Medicine Research Center, The Persian Gulf Biomedical Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Iraj Nabipour
- The Persian Gulf Tropical Medicine Research Center, The Persian Gulf Biomedical Sciences Research Institute, Bushehr University of Medical Sciences, Bushehr, Iran; Future Studies Group, The Academy of Medical Sciences of the I.R., Iran.
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14
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Akhtar S, Benter IF, Danjuma MI, Doi SAR, Hasan SS, Habib AM. Pharmacotherapy in COVID-19 patients: a review of ACE2-raising drugs and their clinical safety. J Drug Target 2020; 28:683-699. [PMID: 32700580 DOI: 10.1080/1061186x.2020.1797754] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The COVID-19 pandemic is caused by the severe acute-respiratory-syndrome-coronavirus-2 that uses ACE2 as its receptor. Drugs that raise serum/tissue ACE2 levels include ACE inhibitors (ACEIs) and angiotensin-II receptor blockers (ARBs) that are commonly used in patients with hypertension, cardiovascular disease and/or diabetes. These comorbidities have adverse outcomes in COVID-19 patients that might result from pharmacotherapy. Increasing ACE2 could potentially increase the risk of infection, severity or mortality in COVID-19 or it might be protective as it forms angiotensin-(1-7) which exhibits anti-inflammatory/anti-oxidative effects and prevents diabetes- and/or hypertension-induced end-organ damage. Thus, there existed clinical uncertainty. Here, we review studies implicating 15 classes of drugs in increasing ACE2 levels in vivo and the available literature on the clinical safety of these drugs in COVID-19 patients. Further, in a re-analysis of clinical data from a meta-analysis of 9 studies, we show that ACEIs/ARBs usage was not associated with an increased risk of all-cause mortality. Literature suggests that ACEIs/ARBs usage generally appears to be clinically safe though their use in severe COVID-19 patients might increase the risk of acute renal injury. For definitive clarity, further clinical and mechanistic studies are needed in assessing the safety of all classes of ACE2 raising medications.
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Affiliation(s)
- Saghir Akhtar
- College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Ibrahim F Benter
- Faculty of Medicine, Eastern Mediterranean University, Famagusta, North Cyprus
| | - Mohammed I Danjuma
- College of Medicine, QU Health, Qatar University, Doha, Qatar.,Division of Internal Medicine, Hamad Medical Corporation Hospital, Doha, Qatar
| | - Suhail A R Doi
- College of Medicine, QU Health, Qatar University, Doha, Qatar
| | - Syed S Hasan
- School of Applied Sciences, University of Huddersfield, Huddersfield, UK
| | - Abdella M Habib
- College of Medicine, QU Health, Qatar University, Doha, Qatar
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15
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Ali FF, Ahmed AF, Elroby Ali DM. Underlying mechanisms behind the protective effect of angiotensin (1–7) in experimental rat model of ovarian ischemia reperfusion injury. Life Sci 2019; 235:116840. [DOI: 10.1016/j.lfs.2019.116840] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 09/02/2019] [Accepted: 09/04/2019] [Indexed: 12/23/2022]
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16
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Loloi J, Miller AJ, Bingaman SS, Silberman Y, Arnold AC. Angiotensin-(1-7) contributes to insulin-sensitizing effects of angiotensin-converting enzyme inhibition in obese mice. Am J Physiol Endocrinol Metab 2018; 315:E1204-E1211. [PMID: 30300010 PMCID: PMC6336955 DOI: 10.1152/ajpendo.00281.2018] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Angiotensin-converting enzyme (ACE) inhibitors reduce body weight, lower blood pressure (BP), and improve insulin sensitivity in animal models of cardiometabolic syndrome. These effects are generally attributed to reduced angiotensin (ANG) II formation; however, these therapies also increase levels of ANG-(1-7), a beneficial hormone opposing ANG II actions. We hypothesized that this ANG-(1-7) generation contributes to the insulin-sensitizing effects of ACE inhibition in obese mice. Adult male C57BL/6J mice were placed on a 60% high-fat diet for 11 wk. During the last 3 wk of diet, mice received normal water or water containing the ACE inhibitor captopril (50 mg/l) as well as the ANG-(1-7) mas receptor antagonist A779 (400 or 800 ng·kg-1·min-1) or saline vehicle via subcutaneous osmotic minipumps. At the end of treatment, arterial BP was measured, and hyperinsulinemic-euglycemic clamps were performed in conscious obese mice receiving vehicle, captopril, captopril plus A779, or A779 ( n = 6-13/group). Captopril reduced body weight (28 ± 2 vs. 41 ± 2 g saline; P = 0.001), lowered systolic BP (109 ± 6 vs. 144 ± 7 mmHg saline; P = 0.041), and improved whole-body insulin sensitivity (steady-state glucose infusion rate: 31 ± 4 vs. 16 ± 2 mg·kg-1·min-1 saline; P = 0.001) in obese mice. A779 attenuated captopril-mediated improvements in insulin sensitivity (23 ± 2 mg·kg-1·min-1; P = 0.042), with no effect on body weight (32 ± 2 g; P = 0.441) or BP (111 ± 7 mmHg; P = 0.788). There was no effect of A779 alone on cardiometabolic outcomes. These data suggest that insulin-sensitizing effects of ACE inhibition are in part due to activation of ANG-(1-7)/ mas receptor pathways and provide new insight into mechanisms underlying the positive metabolic effects of these therapies.
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Affiliation(s)
- Justin Loloi
- Department of Neural and Behavioral Sciences, Pennsylvania State University College of Medicine , Hershey, Pennsylvania
| | - Amanda J Miller
- Department of Neural and Behavioral Sciences, Pennsylvania State University College of Medicine , Hershey, Pennsylvania
| | - Sarah S Bingaman
- Department of Neural and Behavioral Sciences, Pennsylvania State University College of Medicine , Hershey, Pennsylvania
| | - Yuval Silberman
- Department of Neural and Behavioral Sciences, Pennsylvania State University College of Medicine , Hershey, Pennsylvania
| | - Amy C Arnold
- Department of Neural and Behavioral Sciences, Pennsylvania State University College of Medicine , Hershey, Pennsylvania
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17
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Balance and circumstance: The renin angiotensin system in wound healing and fibrosis. Cell Signal 2018; 51:34-46. [PMID: 30071289 DOI: 10.1016/j.cellsig.2018.07.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 07/27/2018] [Accepted: 07/29/2018] [Indexed: 12/17/2022]
Abstract
The tissue renin angiotensin system (tRAS) is a locally-acting master-modulator of tissue homeostasis and regeneration. Through these abilities, it is emerging as an attractive target for therapies aiming to restore tissue homeostasis in conditions associated with disturbed wound healing. The tRAS can be divided into two axes - one being pro-inflammatory and pro-fibrotic and one being anti-inflammatory and anti-fibrotic. However, the division of the axes is fuzzy and imperfect as the axes are codependent and the outcome of tRAS activation is determined by the context. Although the tRAS is a local system it shares its key enzymes, ligands and receptors with the systemic RAS and is consequently also targeted by repurposing of drugs developed against the systemic RAS to manage hypertension. With a focus on the skin we will here discuss the tRAS, its involvement in physiological and pathological wound healing, and the therapeutic aptitude of its targeting to treat chronic wounds and fibrosis.
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18
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Zhang L, Wang J, Liang J, Feng D, Deng F, Yang Y, Lu Y, Hu Z. Propofol prevents human umbilical vein endothelial cell injury from Ang II-induced apoptosis by activating the ACE2-(1-7)-Mas axis and eNOS phosphorylation. PLoS One 2018; 13:e0199373. [PMID: 29995907 PMCID: PMC6040691 DOI: 10.1371/journal.pone.0199373] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Accepted: 06/06/2018] [Indexed: 12/25/2022] Open
Abstract
Angiotensin II (AngII), a vasoactive peptide that elevates arterial blood pressure and results in hypertension, has been reported to directly induce vascular endothelial cell apoptosis. Recent work has demonstrated that propofol pre-treatment attenuates angiotensin II-induced apoptosis in human coronary artery endothelial cells. However, the underlying mechanism remains largely unknown. Here, we investigated human umbilical vein endothelial cells (HUVECs) subjected to angiotensin II-induced apoptosis in the presence or absence of propofol treatment and found that angiotensin II-induced apoptosis was attenuated by propofol in a dose-dependent manner. Furthermore, ELISA assays demonstrated that the ratio of angiotensin (1–7) (Ang (1–7)) to Ang II was increased after propofol treatment. We examined the expression of ACE2, Ang (1–7) and Mas and found that the ACE2-Ang (1–7)-Mas axis was up-regulated by propofol, while ACE2 overexpression increased phosphorylated endothelial nitric oxide synthase (phosphorylated eNOS) expression and siACE2 resulted in the repression of endothelial nitric oxide synthase (eNOS) phosphorylation. In conclusion, our study revealed that propofol can inhibit endothelial cell apoptosis induced by Ang II by activating the ACE2-Ang (1–7)-Mas axis and further up-regulating the expression and phosphorylation of eNOS.
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Affiliation(s)
- Liangqing Zhang
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Jingjing Wang
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Jiuqing Liang
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Du Feng
- Guangdong Key Laboratory of Age-related Cardiac-cerebral Vascular Disease, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Fan Deng
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Yue Yang
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Yue Lu
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Zhe Hu
- Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
- * E-mail:
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19
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Pai WY, Lo WY, Hsu T, Peng CT, Wang HJ. Angiotensin-(1-7) Inhibits Thrombin-Induced Endothelial Phenotypic Changes and Reactive Oxygen Species Production via NADPH Oxidase 5 Downregulation. Front Physiol 2017; 8:994. [PMID: 29375391 PMCID: PMC5770656 DOI: 10.3389/fphys.2017.00994] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 11/20/2017] [Indexed: 01/05/2023] Open
Abstract
Background and Aims: The angiotensin-(1-7)/angiotensin-converting enzyme 2/Mas receptor axis counter-regulates the detrimental effects of angiotensin II. Beneficial effects of angiotensin-(1-7), including anti-inflammation, oxidative stress reduction, and anti-thrombosis, have been reported. Previous studies documented that ramipril decreased thrombin generation in human hypertension and that the anti-thrombotic effects of captopril and losartan were angiotensin-(1-7)-dependent, suggesting an interaction between thrombin and angiotensin-(1-7). However, it is not clear whether angiotensin-(1-7) can alleviate the endothelial phenotypic changes induced by thrombin. We have previously documented cytoskeleton remodeling, cell adhesion, and cell migration as dominant altered phenotypes in thrombin-stimulated human aortic endothelial cells (HAECs). In this study, we investigated whether angiotensin-(1-7) can modulate thrombin-induced phenotypic changes. Furthermore, we investigated whether NAPDH oxidase 5 (Nox5)-produced reactive oxygen species (ROS) play a significant role in angiotensin-(1-7)-mediated phenotypic changes. Methods: HAECs were pretreated with 100 nM angiotensin-(1-7) for 1 h, followed by stimulation with 2 units/mL thrombin for different times. Immunofluorescent assay, monocyte adhesion assay, wound-healing assay, ROS assay, real-time PCR, Western blotting, and Nox5 siRNA transfection were conducted. HAECs were pretreated with the ROS scavenger N-acetylcysteine (NAC) to determine whether thrombin-induced phenotypic changes depended on ROS production. Results: Angiotensin-(1-7) prevented thrombin-induced actin cytoskeleton derangements, monocyte adhesion, and migratory impairment. Nox5 siRNA transfection confirmed that thrombin-induced Nox5 expression stimulated ROS production and increased HO-1/NQO-1/ICAM-1/VCAM-1 gene expression, all of which were decreased by angiotensin-(1-7). Phenotypic changes induced by thrombin were prevented by NAC pretreatment. Conclusion: Angiotensin-(1-7) prevents actin cytoskeleton derangement, monocyte adhesion, and migration impairment induced by thrombin via downregulation of ROS production. In addition, thrombin-induced Nox5 expression is involved in the production of ROS, and angiotensin-(1-7) decreases ROS through its inhibitory effect on Nox5 expression.
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Affiliation(s)
- Wan-Yu Pai
- Department of Bioscience and Biotechnology, Center of Excellence for the Oceans, National Taiwan Ocean University, Keelung, Taiwan
| | - Wan-Yu Lo
- Cardiovascular and Translational Medicine Laboratory, Department of Biotechnology, Hungkuang University, Taichung, Taiwan
| | - Todd Hsu
- Department of Bioscience and Biotechnology, Center of Excellence for the Oceans, National Taiwan Ocean University, Keelung, Taiwan
| | - Ching-Tien Peng
- Department of Pediatrics, Children's Hospital, China Medical University and Hospital, Taichung, Taiwan.,Department of Biotechnology, Asia University, Taichung, Taiwan
| | - Huang-Joe Wang
- Department of Internal Medicine, School of Medicine, China Medical University, Taichung, Taiwan.,Division of Cardiovascular Medicine, Department of Internal Medicine, China Medical University and Hospital, Taichung, Taiwan.,Cardiovascular Research Laboratory, China Medical University and Hospital, Taichung, Taiwan
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20
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Di Bella G, Camastra G, Monti L, Dellegrottaglie S, Piaggi P, Moro C, Pepe A, Lanzillo C, Pontone G, Perazzolo Marra M, Di Roma M, Scatteia A, Aquaro GD. Left and right ventricular morphology, function and late gadolinium enhancement extent and localization change with different clinical presentation of acute myocarditis Data from the ITAlian multicenter study on MYocarditis (ITAMY). J Cardiovasc Med (Hagerstown) 2017; 18:881-887. [DOI: 10.2459/jcm.0000000000000574] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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21
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Salmas RE, Gulhan MF, Durdagi S, Sahna E, Abdullah HI, Selamoglu Z. Effects of propolis, caffeic acid phenethyl ester, and pollen on renal injury in hypertensive rat: An experimental and theoretical approach. Cell Biochem Funct 2017; 35:304-314. [PMID: 28833317 DOI: 10.1002/cbf.3277] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 06/23/2017] [Accepted: 07/03/2017] [Indexed: 12/20/2022]
Abstract
The objective of this study was to evaluate the antioxidant effects of propolis, caffeic acid phenethyl ester (CAPE; active compound in propolis), and pollen on biochemical oxidative stress biomarkers in rat kidney tissue inhibited by Nω -nitro-L-arginine methyl ester (L-NAME). The biomarkers evaluated were paraoxonase (PON1), oxidative stress index (OSI), total antioxidant status (TAS), total oxidant status (TOS), asymmetric dimethylarginine (ADMA), and nuclear factor kappa B (NF-κB). TAS levels and PON1 activity were significantly decreased in kidney tissue samples in the L-NAME-treated group (P < 0.05). The levels of TAS and PONI were higher in the L-NAME plus propolis, CAPE, and pollen groups compared with the L-NAME-treated group. TOS, ADMA, and NF-κB levels were significantly increased in the kidney tissue samples of the L-NAME-treated group (P < 0.05). However, these parameters were significantly lower in the L-NAME plus propolis, CAPE, and pollen groups (P < 0.05) compared with rats administered L-NAME alone (P < 0.05). Furthermore, the binding energy of CAPE within catalytic domain of glutathione reductase (GR) enzyme as well as its inhibitory mechanism was determined using molecular modeling approaches. In conclusion, experimental and theoretical data suggested that oxidative alterations occurring in the kidney tissue of chronic hypertensive rats may be prevented via active compound of propolis, CAPE administration.
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Affiliation(s)
- Ramin Ekhteiari Salmas
- Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey
| | - Mehmet Fuat Gulhan
- Department of Medicinal and Aromatic Plants, Vocational School of Technical Sciences, Aksaray, Turkey
| | - Serdar Durdagi
- Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey
| | - Engin Sahna
- Department of Pharmacology, Faculty of Medicine, Firat University, Elazig, Turkey
| | - Huda I Abdullah
- Department of Medical Biology, Faculty of Medicine, Omer Halisdemir University, Nigde, Turkey
| | - Zeliha Selamoglu
- Department of Medical Biology, Faculty of Medicine, Omer Halisdemir University, Nigde, Turkey
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22
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蔡 少, 陈 景, 陈 美, 林 健, 冯 鉴, 林 凯, 智 喜, 张 伟, 吴 文. [Angiotensin-(1-7) protects cardiac myocytes against high glucose-induced injury by inhibiting ClC-3 chloride channels]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2017; 37:895-901. [PMID: 28736364 PMCID: PMC6765525 DOI: 10.3969/j.issn.1673-4254.2017.07.07] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 05/20/2017] [Indexed: 06/07/2023]
Abstract
OBJECTIVE To explore whether angiotensin-(1-7) [Ang-(1-7)] protects cardiac myocytes against high glucose (HG)-induced injury by inhibiting ClC-3 chloride channels. METHOD H9c2 cardiac cells were exposed to 35 mmol/L glucose for 24 h to establish a cell injury model. The cells were treated with Ang-(1-7) or the inhibitor of chloride channel (NPPB) in the presence of HG for 24 h to observe the changes in HG-induced cell injury. Cell counter kit 8 (CCK-8) assay was used to test the cell viability, and the morphological changes of the apoptotic cells were detected using Hoechst 33258 staining and fluorescent microscopy. The intracellular level of reactive oxygen species (ROS) was examined by DCFH-DA staining, SOD activity in the culture medium was measured using commercial kits, and the mitochondrial membrane potential (MMP) of the cells was tested with rodamine 123 staining. The expression level of cardiac ClC-3 chloride channels was detected with Western blotting. RESULTS Exposure of H9c2 cardiac cells to 35 mmol/L glucose for 24 h markedly enhanced the expressions of cardiac ClC-3 channel protein (P<0.01). Co-treatment of the cells with 1 µmol/L Ang-(1-7) and HG for 24 h significantly attenuated HG- induced upregulation of ClC-3 channel protein expression (P<0.01). Co-treatment of the cells exposed to HG with 1 µmol/L Ang-(1-7) or 100 µmol/L NPPB for 24 h obviously ameliorated HG-induced injuries as shown by increased cell viability, enhanced SOD activity, decreased number of apoptotic cells, and reduced intracellular ROS generation and loss of MMP (P<0.01). CONCLUSION ClC-3 channels are involved in HG-induced injury in cardiac cells. Ang-(1-7) protects cardiac cells against HG-induced injury by inhibiting ClC-3 channels.
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Affiliation(s)
- 少艾 蔡
- 广州医科大学附属第二医院老年科, 广东 广州 510260Department of Geriatrics, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - 景福 陈
- 东莞市第三人民医院心血管内科, 广东 东莞510515Department of Cardiology, Third People's Hospital of Dongguan, Dongguan 510515, China
| | - 美姬 陈
- 中山大学 附属第一医院黄埔院区儿科, 广东广州 510080Department of Pediatrics, Zhongshan Medical College, Sun Yat-sen University, Guangzhou 510080, China
| | - 健聪 林
- 中山大学 附属第一医院黄埔院区内科, 广东广州 510080Department of Internal Medicine, Huangpu Division of First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - 鉴强 冯
- 中山医学院生理学教研室, 广东广州 510080Department of Physiology, Zhongshan Medical College, Sun Yat-sen University, Guangzhou 510080, China
| | - 凯 林
- 广东省人民医院//广东省医学科学院//广东省老年医学研究所东病区内分泌科, 广东 广州 510080Department of Endocrinology, East Ward of Guangdong Geriatric Institute/ Guangdong Academy of Medical Sciences/Guangdong General Hospital, Guangzhou 510080, China
| | - 喜梅 智
- 广东省人民医院//广东省医学科学院//广东省老年医学研究所东病区内分泌科, 广东 广州 510080Department of Endocrinology, East Ward of Guangdong Geriatric Institute/ Guangdong Academy of Medical Sciences/Guangdong General Hospital, Guangzhou 510080, China
| | - 伟杰 张
- 广东省人民医院//广东省医学科学院//广东省老年医学研究所东病区内分泌科, 广东 广州 510080Department of Endocrinology, East Ward of Guangdong Geriatric Institute/ Guangdong Academy of Medical Sciences/Guangdong General Hospital, Guangzhou 510080, China
| | - 文 吴
- 广东省人民医院//广东省医学科学院//广东省老年医学研究所东病区内分泌科, 广东 广州 510080Department of Endocrinology, East Ward of Guangdong Geriatric Institute/ Guangdong Academy of Medical Sciences/Guangdong General Hospital, Guangzhou 510080, China
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Abstract
Inappropriate activation of the renin-angiotensin system (RAS) exacerbates renal and vascular injury. Accordingly, treatment with global RAS antagonists attenuates cardiovascular risk and slows the progression of proteinuric kidney disease. By reducing BP, RAS inhibitors limit secondary immune activation responding to hemodynamic injury in the target organ. However, RAS activation in hematopoietic cells has immunologic effects that diverge from those of RAS stimulation in the kidney and vasculature. In preclinical studies, activating type 1 angiotensin (AT1) receptors in T lymphocytes and myeloid cells blunts the polarization of these cells toward proinflammatory phenotypes, protecting the kidney from hypertensive injury and fibrosis. These endogenous functions of immune AT1 receptors temper the pathogenic actions of renal and vascular AT1 receptors during hypertension. By counteracting the effects of AT1 receptor stimulation in the target organ, exogenous administration of AT2 receptor agonists or angiotensin 1-7 analogs may similarly limit inflammatory injury to the heart and kidney. Moreover, although angiotensin II is the classic effector molecule of the RAS, several RAS enzymes affect immune homeostasis independently of canonic angiotensin II generation. Thus, as reviewed here, multiple components of the RAS signaling cascade influence inflammatory cell phenotype and function with unpredictable and context-specific effects on innate and adaptive immunity.
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Affiliation(s)
- Steven D Crowley
- Division of Nephrology, Department of Medicine, Durham Veterans Affairs and Duke University Medical Centers, Durham, North Carolina
| | - Nathan P Rudemiller
- Division of Nephrology, Department of Medicine, Durham Veterans Affairs and Duke University Medical Centers, Durham, North Carolina
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Angiotensin-(1–7) decreases the expression of collagen I via TGF-β1/Smad2/3 and subsequently inhibits fibroblast–myofibroblast transition. Clin Sci (Lond) 2016; 130:1983-1991. [PMID: 27543459 DOI: 10.1042/cs20160193] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 08/19/2016] [Indexed: 11/17/2022]
Abstract
Previous studies have shown that the RAS (renin–angiotensin system) might participate in airway remodelling in asthma. As a main component of the RAS, Ang-(1–7) [angiotensin-(1–7)] has been reported in few studies regarding its protective effect on asthma. However, the functional roles and relevant signalling pathways of Ang-(1–7) have not been well illustrated. In the present study, we analysed the effect of Ang-(1–7) on AngII (angiotensin II)-induced HLF (human lung fibroblast)–MF (myofibroblast) transition by detecting Col-I (collagen type I), TGF-β1 (transforming growth factor-β1) and α-SMA (α-smooth muscle actin) expression. We explored further the possible signalling pathways involved in HLF–MF transition. Our results showed that Ang-(1–7) could down-regulate the expression of Col-I, α-SMA and TGF-β1/Smad2/3 (all P<0.05). A significant decrease was found in phosphorylation of PI3K (phosphoinositide 3-kinase), Akt, p38-MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase) signalling pathways during HLF–MF transition (all P<0.05). Our data suggests that Ang-(1–7) decreases the expression of Col-I via TGF-β1/Smad2/3 and subsequently inhibits HLF–MF transition.
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Patel VB, Zhong JC, Grant MB, Oudit GY. Role of the ACE2/Angiotensin 1-7 Axis of the Renin-Angiotensin System in Heart Failure. Circ Res 2016; 118:1313-26. [PMID: 27081112 DOI: 10.1161/circresaha.116.307708] [Citation(s) in RCA: 616] [Impact Index Per Article: 68.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 03/19/2016] [Indexed: 11/16/2022]
Abstract
Heart failure (HF) remains the most common cause of death and disability, and a major economic burden, in industrialized nations. Physiological, pharmacological, and clinical studies have demonstrated that activation of the renin-angiotensin system is a key mediator of HF progression. Angiotensin-converting enzyme 2 (ACE2), a homolog of ACE, is a monocarboxypeptidase that converts angiotensin II into angiotensin 1-7 (Ang 1-7) which, by virtue of its actions on the Mas receptor, opposes the molecular and cellular effects of angiotensin II. ACE2 is widely expressed in cardiomyocytes, cardiofibroblasts, and coronary endothelial cells. Recent preclinical translational studies confirmed a critical counter-regulatory role of ACE2/Ang 1-7 axis on the activated renin-angiotensin system that results in HF with preserved ejection fraction. Although loss of ACE2 enhances susceptibility to HF, increasing ACE2 level prevents and reverses the HF phenotype. ACE2 and Ang 1-7 have emerged as a key protective pathway against HF with reduced and preserved ejection fraction. Recombinant human ACE2 has been tested in phase I and II clinical trials without adverse effects while lowering and increasing plasma angiotensin II and Ang 1-7 levels, respectively. This review discusses the transcriptional and post-transcriptional regulation of ACE2 and the role of the ACE2/Ang 1-7 axis in cardiac physiology and in the pathophysiology of HF. The pharmacological and therapeutic potential of enhancing ACE2/Ang 1-7 action as a novel therapy for HF is highlighted.
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Affiliation(s)
- Vaibhav B Patel
- From the Division of Cardiology, Department of Medicine (V.B.P., G.Y.O.), Mazankowski Alberta Heart Institute (V.B.P., G.Y.O.), and Department of Physiology (G.Y.O.), University of Alberta, Edmonton, Canada; State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.-C.Z.); Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, China (J.-C.Z.); and Department of Ophthalmology, Indiana University School of Medicine, Indianapolis (M.B.G.)
| | - Jiu-Chang Zhong
- From the Division of Cardiology, Department of Medicine (V.B.P., G.Y.O.), Mazankowski Alberta Heart Institute (V.B.P., G.Y.O.), and Department of Physiology (G.Y.O.), University of Alberta, Edmonton, Canada; State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.-C.Z.); Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, China (J.-C.Z.); and Department of Ophthalmology, Indiana University School of Medicine, Indianapolis (M.B.G.)
| | - Maria B Grant
- From the Division of Cardiology, Department of Medicine (V.B.P., G.Y.O.), Mazankowski Alberta Heart Institute (V.B.P., G.Y.O.), and Department of Physiology (G.Y.O.), University of Alberta, Edmonton, Canada; State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.-C.Z.); Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, China (J.-C.Z.); and Department of Ophthalmology, Indiana University School of Medicine, Indianapolis (M.B.G.)
| | - Gavin Y Oudit
- From the Division of Cardiology, Department of Medicine (V.B.P., G.Y.O.), Mazankowski Alberta Heart Institute (V.B.P., G.Y.O.), and Department of Physiology (G.Y.O.), University of Alberta, Edmonton, Canada; State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.-C.Z.); Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, China (J.-C.Z.); and Department of Ophthalmology, Indiana University School of Medicine, Indianapolis (M.B.G.).
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Simões E Silva AC, Teixeira MM. ACE inhibition, ACE2 and angiotensin-(1-7) axis in kidney and cardiac inflammation and fibrosis. Pharmacol Res 2016; 107:154-162. [PMID: 26995300 DOI: 10.1016/j.phrs.2016.03.018] [Citation(s) in RCA: 168] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 03/03/2016] [Accepted: 03/14/2016] [Indexed: 12/21/2022]
Abstract
The Renin Angiotensin System (RAS) is a pivotal physiological regulator of heart and kidney homeostasis, but also plays an important role in the pathophysiology of heart and kidney diseases. Recently, new components of the RAS have been discovered, including angiotensin converting enzyme 2 (ACE2), Angiotensin(Ang)-(1-7), Mas receptor, Ang-(1-9) and Alamandine. These new components of RAS are formed by the hydrolysis of Ang I and Ang II and, in general, counteract the effects of Ang II. In experimental models of heart and renal diseases, Ang-(1-7), Ang-(1-9) and Alamandine produced vasodilation, inhibition of cell growth, anti-thrombotic, anti-inflammatory and anti-fibrotic effects. Recent pharmacological strategies have been proposed to potentiate the effects or to enhance the formation of Ang-(1-7) and Ang-(1-9), including ACE2 activators, Ang-(1-7) in hydroxypropyl β-cyclodextrin, cyclized form of Ang-(1-7) and nonpeptide synthetic Mas receptor agonists. Here, we review the role and effects of ACE2, ACE2 activators, Ang-(1-7) and synthetic Mas receptor agonists in the control of inflammation and fibrosis in cardiovascular and renal diseases and as counter-regulators of the ACE-Ang II-AT1 axis. We briefly comment on the therapeutic potential of the novel members of RAS, Ang-(1-9) and alamandine, and the interactions between classical RAS inhibitors and new players in heart and kidney diseases.
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Affiliation(s)
- Ana Cristina Simões E Silva
- Laboratório Interdisciplinar de Investigação Médica, Unidade de Nefrologia Pediátrica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Brazil.
| | - Mauro Martins Teixeira
- Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, ICB, UFMG, Brazil
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Akhtar S, Chandrasekhar B, Attur S, Dhaunsi GS, Yousif MHM, Benter IF. Transactivation of ErbB Family of Receptor Tyrosine Kinases Is Inhibited by Angiotensin-(1-7) via Its Mas Receptor. PLoS One 2015; 10:e0141657. [PMID: 26536590 PMCID: PMC4633289 DOI: 10.1371/journal.pone.0141657] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 10/12/2015] [Indexed: 01/03/2023] Open
Abstract
Transactivation of the epidermal growth factor receptor (EGFR or ErbB) family members, namely EGFR and ErbB2, appears important in the development of diabetes-induced vascular dysfunction. Angiotensin-(1–7) [Ang-(1–7)] can prevent the development of hyperglycemia-induced vascular complications partly through inhibiting EGFR transactivation. Here, we investigated whether Ang-(1–7) can inhibit transactivation of ErbB2 as well as other ErbB receptors in vivo and in vitro. Streptozotocin-induced diabetic rats were chronically treated with Ang-(1–7) or AG825, a selective ErbB2 inhibitor, for 4 weeks and mechanistic studies performed in the isolated mesenteric vasculature bed as well as in cultured vascular smooth muscle cells (VSMCs). Ang-(1–7) or AG825 treatment inhibited diabetes-induced phosphorylation of ErbB2 receptor at tyrosine residues Y1221/22, Y1248, Y877, as well as downstream signaling via ERK1/2, p38 MAPK, ROCK, eNOS and IkB-α in the mesenteric vascular bed. In VSMCs cultured in high glucose (25 mM), Ang-(1–7) inhibited src-dependent ErbB2 transactivation that was opposed by the selective Mas receptor antagonist, D-Pro7-Ang-(1–7). Ang-(1–7) via Mas receptor also inhibited both Angiotensin II- and noradrenaline/norephinephrine-induced transactivation of ErbB2 and/or EGFR receptors. Further, hyperglycemia-induced transactivation of ErbB3 and ErbB4 receptors could be attenuated by Ang-(1–7) that could be prevented by D-Pro7-Ang-(1–7) in VSMC. These data suggest that Ang-(1–7) via its Mas receptor acts as a pan-ErbB inhibitor and might represent a novel general mechanism by which Ang-(1–7) exerts its beneficial effects in many disease states including diabetes-induced vascular complications.
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MESH Headings
- Angiotensin I/pharmacology
- Animals
- Blotting, Western
- Cells, Cultured
- Diabetes Mellitus, Experimental/drug therapy
- Diabetes Mellitus, Experimental/genetics
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Experimental/pathology
- Diabetes Mellitus, Type 1/drug therapy
- Diabetes Mellitus, Type 1/genetics
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 1/pathology
- ErbB Receptors/antagonists & inhibitors
- ErbB Receptors/genetics
- Gene Expression Regulation/drug effects
- Glucose/metabolism
- Male
- Muscle, Smooth, Vascular/cytology
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/metabolism
- Peptide Fragments/pharmacology
- Phosphorylation
- Proto-Oncogene Mas
- Proto-Oncogene Proteins/metabolism
- Rats
- Rats, Wistar
- Receptors, G-Protein-Coupled/metabolism
- Signal Transduction
- Transcriptional Activation/drug effects
- Vasodilator Agents/pharmacology
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Affiliation(s)
- Saghir Akhtar
- Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Safat 13110, Kuwait
- * E-mail:
| | - Bindu Chandrasekhar
- Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Safat 13110, Kuwait
| | - Sreeja Attur
- Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Safat 13110, Kuwait
| | - Gursev S. Dhaunsi
- Department of Pediatrics, Faculty of Medicine, Kuwait University, Safat 13110, Kuwait
| | - Mariam H. M. Yousif
- Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Safat 13110, Kuwait
| | - Ibrahim F. Benter
- Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Safat 13110, Kuwait
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Abwainy A, Babiker F, Akhtar S, Benter IF. Endogenous angiotensin-(1-7)/Mas receptor/NO pathway mediates the cardioprotective effects of pacing postconditioning. Am J Physiol Heart Circ Physiol 2015; 310:H104-12. [PMID: 26519026 DOI: 10.1152/ajpheart.00121.2015] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Accepted: 10/08/2015] [Indexed: 11/22/2022]
Abstract
The aim of the present study was to investigate the role of the ANG-(1-7) receptor (Mas) and nitric oxide (NO) in pacing postconditiong (PPC)-mediated cardioprotection against ischemia-reperfusion injury. Cardiac contractility and hemodynamics were assessed using a modified Langendorff system, cardiac damage was assessed by measuring infarct size and creatinine kinase levels, and levels of phosphorylated and total endothelial NO synthase (eNOS) were determined by Western blot analysis. Isolated hearts were subjected to 30 min of regional ischemia, produced by fixed position ligation of the left anterior descending coronary artery, followed by 30 min of reperfusion (n = 6). Hearts were also subjected to PPC (three cycles of 30 s of left ventricular pacing alternated with 30 s of right atrial pacing) and/or treated during reperfusion with ANG-(1-7), N(G)-nitro-l-arginine methyl ester, or the Mas antagonist (d-Ala7)-ANG I/II (1-7). The PPC-mediated improvement in cardiac contractility and hemodyanamics, cardiac damage, and eNOS phosphorylation were significantly attenuated upon treatment with (d-Ala7)-ANG I/II (1-7) or N(G)-nitro-l-arginine methyl ester. Treatment with ANG-(1-7) improved cardiac function and reduced infarct size and creatinine kinase levels; however, the effects of ANG-(1-7) were not additive with PPC. In conclusion, these data provide novel insights into the cardioprotective mechanisms of PPC in that they involve the Mas receptor and eNOS and further suggest a potential therapeutic role for ANG-(1-7) in cardiac ischemic injury.
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Affiliation(s)
- Ala'a Abwainy
- Department of Physiology, Faculty of Medicine, Health Science Center, Kuwait University, Kuwait
| | - Fawzi Babiker
- Department of Physiology, Faculty of Medicine, Health Science Center, Kuwait University, Kuwait;
| | - Saghir Akhtar
- Department of Pharmacology, Faculty of Medicine, Health Science Center, Kuwait University, Kuwait; and
| | - Ibrahim F Benter
- Faculty of Medicine, Eastern Mediterranean University, Famagusta, North Cyprus
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Zheng H, Pu SY, Fan XF, Li XS, Zhang Y, Yuan J, Zhang YF, Yang JL. Treatment with angiotensin-(1-9) alleviates the cardiomyopathy in streptozotocin-induced diabetic rats. Biochem Pharmacol 2015; 95:38-45. [DOI: 10.1016/j.bcp.2015.03.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 03/13/2015] [Indexed: 02/07/2023]
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Fu H, Li G, Liu C, Li J, Wang X, Cheng L, Liu T. Probucol prevents atrial remodeling by inhibiting oxidative stress and TNF-α/NF-κB/TGF-β signal transduction pathway in alloxan-induced diabetic rabbits. J Cardiovasc Electrophysiol 2015; 26:211-222. [PMID: 25199622 DOI: 10.1111/jce.12540] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2014] [Revised: 08/16/2014] [Accepted: 09/02/2014] [Indexed: 01/01/2023]
Abstract
INTRODUCTION Diabetes mellitus (DM) is an independent risk factor for atrial fibrillation (AF). However, the underlying mechanisms for the increased propensity for AF in the setting of DM and the potential effects of probucol on atrial remodeling remain unclear. METHODS AND RESULTS Eighty Japanese rabbits were randomly assigned to normal/control group (Control, n = 20), alloxan-induced diabetic group (DM, n = 20), probucol-treated group (Control-P, n = 20), and probucol-treated diabetic group (DM-P, n = 20). Rabbits in the DPR and CPR groups were orally administered probucol (1,000 mg/day) for 8 weeks. Serum and left atrial tissue malonaldehyde (MDA), superoxide dismutase (SOD), myeloperoxidase (MPO), and catalase (CAT) levels were assessed. Isolated Langendorff perfused rabbit hearts were prepared to evaluate atrial refractory effective period (AERP) and its dispersion (AERPD), interatrial conduction time (IACT), and vulnerability to AF. Atrial interstitial fibrosis was also evaluated. The mRNA expression levels of TNF-α and TLR4 were analyzed. The protein expressions of NF-κB, HSP70, TGF-β, and ERK in left atrial tissue were analyzed by Western blot. Probucol administration decreased the inducibility of AF in diabetic rabbits and attenuated atrial interstitial fibrosis. The DM-P rabbits exhibited significant alleviation of oxidative stress, evidenced by reduced serum and tissue MDA, compared with diabetic rabbits. Moreover, NF-κB, TGF-β, and HSP70 protein expression and TNF-α mRNA expression were significantly downregulated by probucol treatment in alloxan-induced diabetic rabbits. CONCLUSIONS Probucol prevents atrial remodeling and suppresses AF development in alloxan-induced diabetic rabbits. Its inhibitory effects on oxidative stress, NF-κB, TGF-β, and TNF-α overexpression may contribute to its antiremodeling effects.
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Affiliation(s)
- Huaying Fu
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, People's Republic of China
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Rizk SM, El-Maraghy SA, Nassar NN. A novel role for SIRT-1 in L-arginine protection against STZ induced myocardial fibrosis in rats. PLoS One 2014; 9:e114560. [PMID: 25501750 PMCID: PMC4264750 DOI: 10.1371/journal.pone.0114560] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2014] [Accepted: 11/11/2014] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND L-arginine (L-ARG) effectively protects against diabetic impediments. In addition, silent information regulator (SIRT-1) activators are emerging as a new clinical concept in treating diabetic complications. Accordingly, this study aimed at delineating a role for SIRT-1 in mediating L-ARG protection against streptozotocin (STZ) induced myocardial fibrosis. METHODS Male Wistar rats were allocated into five groups; (i) normal control rats received 0.1 M sodium citrate buffer (pH 4.5); (ii) STZ at the dose of 60 mg/kg dissolved in 0.1 M sodium citrate buffer (pH 4.5); (iii) STZ + sirtinol (Stnl; specific inhibitor of SIRT-1; 2 mg/Kg, i.p.); (iv) STZ + L-ARG given in drinking water (2.25%) or (v) STZ + L-ARG + Stnl. RESULTS L-ARG increased myocardial SIRT-1 expression as well as its protein content. The former finding was paralleled by L-ARG induced reduction in myocardial fibrotic area compared to STZ animals evidenced histopathologically. The reduction in the fibrotic area was accompanied by a decline in fibrotic markers as evident by a decrease in expression of collagen-1 along with reductions in myocardial TGF-β, fibronectin, CTGF and BNP expression together with a decrease in TGF-β and hydroxyproline contents. Moreover, L-ARG increased MMP-2 expression in addition to its protein content while decreasing expression of PAI-1. Finally, L-ARG protected against myocardial cellular death by reduction in NFκ-B mRNA as well as TNF-α level in association with decline in Casp-3 and FAS expressions andCasp-3protein content in addition to reduction of FAS positive cells. However, co-administration of L-ARG and Stnl diminished the protective effect of L-ARG against STZ induced myocardial fibrosis. CONCLUSION Collectively, these findings associate a role for SIRT-1 in L-ARG defense against diabetic cardiac fibrosis via equilibrating the balance between profibrotic and antifibrotic mediators.
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Affiliation(s)
- Sherine M. Rizk
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | | | - Noha N. Nassar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
- * E-mail:
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Bader M, Alenina N, Andrade-Navarro MA, Santos RA. MAS and its related G protein-coupled receptors, Mrgprs. Pharmacol Rev 2014; 66:1080-105. [PMID: 25244929 DOI: 10.1124/pr.113.008136] [Citation(s) in RCA: 137] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
The Mas-related G protein-coupled receptors (Mrgprs or Mas-related genes) comprise a subfamily of receptors named after the first discovered member, Mas. For most Mrgprs, pruriception seems to be the major function based on the following observations: 1) they are relatively promiscuous in their ligand specificity with best affinities for itch-inducing substances; 2) they are expressed in sensory neurons and mast cells in the skin, the main cellular components of pruriception; and 3) they appear in evolution first in tetrapods, which have arms and legs necessary for scratching to remove parasites or other noxious substances from the skin before they create harm. Because parasites coevolved with hosts, each species faced different parasitic challenges, which may explain another striking observation, the multiple independent duplication and expansion events of Mrgpr genes in different species as a consequence of parallel adaptive evolution. Their predominant expression in dorsal root ganglia anticipates additional functions of Mrgprs in nociception. Some Mrgprs have endogenous ligands, such as β-alanine, alamandine, adenine, RF-amide peptides, or salusin-β. However, because the functions of these agonists are still elusive, the physiologic role of the respective Mrgprs needs to be clarified. The best studied Mrgpr is Mas itself. It was shown to be a receptor for angiotensin-1-7 and to exert mainly protective actions in cardiovascular and metabolic diseases. This review summarizes the current knowledge about Mrgprs, their evolution, their ligands, their possible physiologic functions, and their therapeutic potential.
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Affiliation(s)
- Michael Bader
- Max-Delbrück-Center for Molecular Medicine, Berlin, Germany (M.B., N.A., M.A.A.-N.); Charité-University Medicine, Berlin, Germany (M.B.); Institute for Biology, University of Lübeck, Lübeck, Germany (M.B.); and Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Brazil (M.B., N.A., R.A.S.)
| | - Natalia Alenina
- Max-Delbrück-Center for Molecular Medicine, Berlin, Germany (M.B., N.A., M.A.A.-N.); Charité-University Medicine, Berlin, Germany (M.B.); Institute for Biology, University of Lübeck, Lübeck, Germany (M.B.); and Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Brazil (M.B., N.A., R.A.S.)
| | - Miguel A Andrade-Navarro
- Max-Delbrück-Center for Molecular Medicine, Berlin, Germany (M.B., N.A., M.A.A.-N.); Charité-University Medicine, Berlin, Germany (M.B.); Institute for Biology, University of Lübeck, Lübeck, Germany (M.B.); and Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Brazil (M.B., N.A., R.A.S.)
| | - Robson A Santos
- Max-Delbrück-Center for Molecular Medicine, Berlin, Germany (M.B., N.A., M.A.A.-N.); Charité-University Medicine, Berlin, Germany (M.B.); Institute for Biology, University of Lübeck, Lübeck, Germany (M.B.); and Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Brazil (M.B., N.A., R.A.S.)
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Abstract
Although heart disease due to diabetes is mainly associated with complications of the large vessels, microvascular abnormalities are also considered to be involved in altering cardiac structure and function. Three major defects, such as endothelial dysfunction, alteration in the production/release of hormones, and shift in metabolism of smooth muscle cells, have been suggested to produce damage to the small arteries and capillaries (microangiopathy) due to hyperglycemia, and promote the development of diabetic cardiomyopathy. These factors may either act alone or in combination to produce oxidative stress as well as changes in cellular signaling and gene transcription, which in turn cause vasoconstriction and structural remodeling of the coronary vessels. Such alterations in microvasculature produce hypoperfusion of the myocardium and thereby lower the energy status resulting in changes in Ca(2+)-handling, apoptosis, and decreased cardiac contractile force. This article discusses diabetes-induced mechanisms of microvascular damage leading to cardiac dysfunction that is characterized by myocardial dilatation, cardiac hypertrophy as well as early diastolic and late systolic defects. Metabolic defects and changes in neurohumoral system due to diabetes, which promote disturbances in vascular homeostasis, are highlighted. In addition, increase in the vulnerability of the diabetic heart to the development of heart failure and the signaling pathways integrating nuclear factor κB and protein kinase C in diabetic cardiomyopathy are also described for comparison.
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Affiliation(s)
- Adriana Adameova
- Institute of Cardiovascular Sciences, Department of Physiology, Faculty of Medicine, University of Manitoba, St. Boniface Hospital Research, 351 Tache Avenue, Winnipeg, MB, R2H 2A6, Canada
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Manchini MT, Serra AJ, Feliciano RDS, Santana ET, Antônio EL, de Tarso Camillo de Carvalho P, Montemor J, Crajoinas RO, Girardi ACC, Tucci PJF, Silva JA. Amelioration of cardiac function and activation of anti-inflammatory vasoactive peptides expression in the rat myocardium by low level laser therapy. PLoS One 2014; 9:e101270. [PMID: 24991808 PMCID: PMC4081549 DOI: 10.1371/journal.pone.0101270] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Accepted: 06/05/2014] [Indexed: 11/18/2022] Open
Abstract
Low-level laser therapy (LLLT) has been used as an anti-inflammatory treatment in several disease conditions, even when inflammation is a secondary consequence, such as in myocardial infarction (MI). However, the mechanism by which LLLT is able to protect the remaining myocardium remains unclear. The present study tested the hypothesis that LLLT reduces inflammation after acute MI in female rats and ameliorates cardiac function. The potential participation of the Renin-Angiotensin System (RAS) and Kallikrein-Kinin System (KKS) vasoactive peptides was also evaluated. LLLT treatment effectively reduced MI size, attenuated the systolic dysfunction after MI, and decreased the myocardial mRNA expression of interleukin-1 beta and interleukin-6 in comparison to the non-irradiated rat tissue. In addition, LLLT treatment increased protein and mRNA levels of the Mas receptor, the mRNA expression of kinin B2 receptors and the circulating levels of plasma kallikrein compared to non-treated post-MI rats. On the other hand, the kinin B1 receptor mRNA expression decreased after LLLT. No significant changes were found in the expression of vascular endothelial growth factor (VEGF) in the myocardial remote area between laser-irradiated and non-irradiated post-MI rats. Capillaries density also remained similar between these two experimental groups. The mRNA expression of the inducible nitric oxide synthase (iNOS) was increased three days after MI, however, this effect was blunted by LLLT. Moreover, endothelial NOS mRNA content increased after LLLT. Plasma nitric oxide metabolites (NOx) concentration was increased three days after MI in non-treated rats and increased even further by LLLT treatment. Our data suggest that LLLT diminishes the acute inflammation in the myocardium, reduces infarct size and attenuates left ventricle dysfunction post-MI and increases vasoactive peptides expression and nitric oxide (NO) generation.
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Affiliation(s)
| | | | | | | | | | | | - Jairo Montemor
- Universidade Federal de São Paulo, UNIFESP, São Paulo, SP, Brasil
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Liu R, Qi H, Wang J, Wang Y, Cui L, Wen Y, Yin C. Ulinastatin activates the renin-angiotensin system to ameliorate the pathophysiology of severe acute pancreatitis. J Gastroenterol Hepatol 2014; 29:1328-37. [PMID: 24628092 DOI: 10.1111/jgh.12584] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/28/2014] [Indexed: 01/13/2023]
Abstract
BACKGROUND AND AIM Ulinastatin is a drug used effectively to alleviate symptoms and improve the pathophysiology of various types of pancreatitis. However, the molecular mechanism responsible for its action remains unknown. Therefore, we further explore the therapeutic effects of ulinastatin and investigate possible molecular pathways modulated by this drug in the development of severe acute pancreatitis (SAP). METHODS SAP mouse model was created by administering intraperitoneal injections of cerulein and lipopolysaccharide. Pancreatic injury was assessed by performing biochemical and histological assays and by measuring the inflammatory response of the pancreas. Specifically, we examined changes in the expression of components of the rennin-angiotensin system (RAS), including angiotensin-converting enzyme (ACE)-angiotensin II (Ang II)-angiotensin type 1 receptor (AT-1R), and ACE2-Ang-(1-7)-Mas receptor. RESULTS When SAP mouse models were treated with ulinastatin at a dosage of 50,000 U/kg body weight, we found, through biochemical and histopathological analyses, that the pancreatic injury was significantly ameliorated. Administration of ulinastatin to SAP mice led to increased expression of ACE2, Ang-(1-7), and Mas receptor, decreased expression of serum Ang II and pancreatic AT-1R, and no alterations in the expression of pancreatic ACE and Ang II when compared to cerulein-treated control group that did not receive ulinastatin. CONCLUSIONS This study shows that ulinastatin has differential effects on the two axes of the RAS during SAP. Our results further suggest that upregulation of components of the ACE2-Ang-(1-7)-Mas pathway might be an important mechanism contributing to the therapeutic role of ulinastatin in alleviating pancreatitis-associated symptoms.
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Affiliation(s)
- Ruixia Liu
- Department of Infection, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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Zimmerman MA, Harris RA, Sullivan JC. Female spontaneously hypertensive rats are more dependent on ANG (1-7) to mediate effects of low-dose AT1 receptor blockade than males. Am J Physiol Renal Physiol 2014; 306:F1136-42. [PMID: 24647710 DOI: 10.1152/ajprenal.00677.2013] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
ANG (1-7) contributes to the blood pressure (BP)-lowering effect of angiotensin receptor blockers (ARBs) in male experimental animals. Females have greater ANG (1-7) concentrations than males; however, the contribution of ANG (1-7) to ARB-mediated decreases in BP in females is unknown. The current study tested the hypothesis that female spontaneously hypertensive rats (SHR) have a larger ANG (1-7) contribution to the BP-lowering effects of the ARB candesartan than male SHR. Twelve-week-old male and female SHR were randomized to receive candesartan (0.5 mg·kg(-1)·day(-1); 7 days), candesartan plus ANG II (200 ng·kg(-1)·min(-1); 7 days), the ANG (1-7) antagonist A-779 (48 μg·kg(-1)·h(-1)) plus candesartan and ANG II. Candesartan decreased basal BP in males and females (baseline vs. candesartan: 142 ± 2 vs. 122 ± 3 and 129 ± 1 vs. 115 ± 1 mmHg, respectively; P < 0.05); however, the decrease was greater in males. ANG II increased BP in males in the presence of candesartan (149 ± 2 mmHg; P < 0.05); candesartan blocked ANG II-induced increases in BP in females (116 ± 1 mmHg). Pretreatment with A-779 abolished candesartan-mediated decreases in BP in females, but not males. A-779 also exacerbated ANG II-induced proteinuria (26 ± 6 vs. 77 ± 11 μg·kg(-1)·day(-1), respectively; P < 0.05) and nephrinuria (20 ± 5 vs. 202 ± 58 μg·kg(-1)·day(-1), respectively; P < 0.05) in candesartan-treated female SHR, with no effect in males. In conclusion, females are more sensitive to the BP-lowering effect of ARBs during ANG II infusion, whereas males are more sensitive under basal conditions. In addition, ANG (1-7) has a greater contribution to ARB-mediated decreases in BP, protein, and nephrin excretion in females relative to males.
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Affiliation(s)
| | - Ryan A Harris
- Georgia Prevention Center, Georgia Regents University, Augusta, Georgia; and Sport and Exercise Science Research Institute, University of Ulster, Northern Ireland, United Kingdom
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Nekooeian AA, Khalili A, Khosravi MB. Effects of Short-term Renovascular Hypertension and Type 2 Diabetes on Cardiac Functions in Rats. IRANIAN JOURNAL OF MEDICAL SCIENCES 2014; 39:51-9. [PMID: 24453394 PMCID: PMC3895895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2012] [Revised: 12/30/2012] [Accepted: 01/13/2013] [Indexed: 11/26/2022]
Abstract
BACKGROUND The cardiac effects simultaneously occurring during experimental hypertension and diabetes have rarely been investigated. This study aimed at examining the effects of short-term renovascular hypertension and type 2 diabetes on cardiac functions. METHODS Five groups (7 each) of male Sprague-Dawley rats, including a control group, a diabetes (induced by Streptozocin and Nicotinamide) group, a renovascular hypertensive (induced by placing Plexiglas clips on the left renal arteries) group, a sham group, and a simultaneously hypertensive-diabetic group, were used. The animals' hearts were used for isolated heart studies, and the indices of cardiac functions and coronary effluent creatine kinase MB were measured. The results were analyzed using One-way Analysis of Variance, followed by the Duncan Multiple Range test. RESULTS The diabetic group had a significantly lower rate of rise (-29.5%) and decrease (-36.18%) in ventricular pressure, left ventricular developed pressure (-28.8%), and rate pressure product (-35%), and significantly higher creatine kinase MB (+166%) and infarct size (+36.2%) than those of the control group. The hypertensive group had a significantly higher rate of rise (+12.17%) and decrease (+16.2%) in ventricular pressure, left ventricular developed pressure (+16%), and rate pressure product (+24%), and significantly lower creatine kinase MB (-30%) and infarct size (-27%) than those of the sham group. Simultaneously, the diabetic and hypertensive rats had a significantly higher rate of rise (+32%) and decrease (+30.2%) in ventricular pressure, left ventricular developed pressure (+17.2%), and rate pressure product (+22.2%), and significantly lower creatine kinase MB (-24%) and infarct size (-16.2%) than those of the diabetic group. CONCLUSION The findings indicated that the simultaneity of hypertension with type 2 diabetes attenuated diabetes-induced cardiac impairment.
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Affiliation(s)
- Ali Akbar Nekooeian
- Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran;
,Cardiovascular Pharmacology Research Center, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran;
| | - Azadeh Khalili
- Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran;
| | - Mohammad Bagher Khosravi
- Cardiovascular Pharmacology Research Center, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran;
,Department of Anesthesiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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Role of angiotensin-converting enzyme 2 (ACE2) in diabetic cardiovascular complications. Clin Sci (Lond) 2013; 126:471-82. [DOI: 10.1042/cs20130344] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Diabetes mellitus results in severe cardiovascular complications, and heart disease and failure remain the major causes of death in patients with diabetes. Given the increasing global tide of obesity and diabetes, the clinical burden of diabetes-induced cardiovascular disease is reaching epidemic proportions. Therefore urgent actions are needed to stem the tide of diabetes which entails new prevention and treatment tools. Clinical and pharmacological studies have demonstrated that AngII (angiotensin II), the major effector peptide of the RAS (renin–angiotensin system), is a critical promoter of insulin resistance and diabetes mellitus. The role of RAS and AngII has been implicated in the progression of diabetic cardiovascular complications and AT1R (AngII type 1 receptor) blockers and ACE (angiotensin-converting enzyme) inhibitors have shown clinical benefits. ACE2, the recently discovered homologue of ACE, is a monocarboxypeptidase which converts AngII into Ang-(1–7) [angiotensin-(1–7)] which, by virtue of its actions on the MasR (Mas receptor), opposes the effects of AngII. In animal models of diabetes, an early increase in ACE2 expression and activity occurs, whereas ACE2 mRNA and protein levels have been found to decrease in older STZ (streptozotocin)-induced diabetic rats. Using the Akita mouse model of Type 1 diabetes, we have recently shown that loss of ACE2 disrupts the balance of the RAS in a diabetic state and leads to AngII/AT1R-dependent systolic dysfunction and impaired vascular function. In the present review, we will discuss the role of the RAS in the pathophysiology and treatment of diabetes and its complications with particular emphasis on potential benefits of the ACE2/Ang-(1–7)/MasR axis activation.
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Palomer X, Salvadó L, Barroso E, Vázquez-Carrera M. An overview of the crosstalk between inflammatory processes and metabolic dysregulation during diabetic cardiomyopathy. Int J Cardiol 2013; 168:3160-72. [PMID: 23932046 DOI: 10.1016/j.ijcard.2013.07.150] [Citation(s) in RCA: 222] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Accepted: 07/15/2013] [Indexed: 10/26/2022]
Abstract
Metabolic disorders such as obesity, insulin resistance and type 2 diabetes mellitus are all linked to cardiovascular diseases such as cardiac hypertrophy and heart failure. Diabetic cardiomyopathy in particular, is characterized by structural and functional alterations in the heart muscle of people with diabetes that finally lead to heart failure, and which is not directly attributable to coronary artery disease or hypertension. Several mechanisms have been involved in the pathogenesis of diabetic cardiomyopathy, such as alterations in myocardial energy metabolism and calcium signaling. Metabolic disturbances during diabetic cardiomyopathy are characterized by increased lipid oxidation, intramyocardial triglyceride accumulation, and reduced glucose utilization. Overall changes result in enhanced oxidative stress, mitochondrial dysfunction and apoptosis of the cardiomyocytes. On the other hand, the progression of heart failure and cardiac hypertrophy usually entails a local rise in cytokines in cardiac cells and the activation of the proinflammatory transcription factor nuclear factor (NF)-κB. Interestingly, increasing evidences are arising in the recent years that point to a potential link between chronic low-grade inflammation in the heart and metabolic dysregulation. Therefore, in this review we summarize recent new insights into the crosstalk between inflammatory processes and metabolic dysregulation in the failing heart during diabetes, paying special attention to the role of NF-κB and peroxisome proliferator activated receptors (PPARs). In addition, we briefly describe the role of the AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1) and other pathways regulating cardiac energy metabolism, as well as their relationship with diabetic cardiomyopathy.
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Affiliation(s)
- Xavier Palomer
- Department of Pharmacology and Therapeutic Chemistry, IBUB (Institut de Biomedicina de la Universitat de Barcelona), Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Faculty of Pharmacy, University of Barcelona, Diagonal 643, Barcelona E-08028, Spain
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Kilarkaje N, Yousif MH, El-Hashim AZ, Makki B, Akhtar S, Benter IF. Role of angiotensin II and angiotensin-(1–7) in diabetes-induced oxidative DNA damage in the corpus cavernosum. Fertil Steril 2013; 100:226-33. [DOI: 10.1016/j.fertnstert.2013.02.046] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Revised: 02/19/2013] [Accepted: 02/26/2013] [Indexed: 12/17/2022]
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Clarke C, Flores-Muñoz M, McKinney CA, Milligan G, Nicklin SA. Regulation of cardiovascular remodeling by the counter-regulatory axis of the renin-angiotensin system. Future Cardiol 2013; 9:23-38. [PMID: 23259473 DOI: 10.2217/fca.12.75] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The counter-regulatory axis of the renin-angiotensin system (RAS) is a novel therapeutic target in cardiovascular disease. Pathophysiological effects mediated via angiotensin II (Ang II) are well established in regulation of blood pressure, cardiac and vascular remodeling, and renal sodium handling, which lead to disorders such as hypertension and associated end-organ damage, atherosclerosis and heart failure. The counter-regulatory axis of the RAS is centered on the angiotensin-converting enzyme 2/angiotensin-1-7 (Ang-[1-7])/Mas receptor axis and has been shown to inhibit many detrimental phenotypes in cardiovascular disease. More recently, an alternative peptide, angiotensin-(1-9) (Ang-[1-9]), has been reported as a potential new member of this axis. This review will discuss the cardiovascular regulatory roles of Ang-(1-7) and Ang-(1-9) in the counter-regulatory axis of the RAS, and the potential for new therapeutic approaches in cardiovascular disease.
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Affiliation(s)
- Carolyn Clarke
- Institute of Cardiovascular & Medical Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, BHF Glasgow Cardiovascular Research Centre, 126 University Place, University of Glasgow, G12 8TA, UK
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Varagic J, Ahmad S, VonCannon JL, Moniwa N, Brosnihan KB, Wysocki J, Batlle D, Ferrario CM. Predominance of AT(1) blockade over mas-mediated angiotensin-(1-7) mechanisms in the regulation of blood pressure and renin-angiotensin system in mRen2.Lewis rats. Am J Hypertens 2013; 26:583-90. [PMID: 23459599 DOI: 10.1093/ajh/hps090] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND We investigated whether the antihypertensive actions of the angiotensin II (Ang II) receptor (AT(1)-R) blocker, olmesartan medoxomil, may in part be mediated by increased Ang-(1-7) in the absence of significant changes in plasma Ang II. METHODS mRen2.Lewis congenic hypertensive rats were administered either a vehicle (n = 14) or olmesartan (0.5 mg/kg/day; n = 14) by osmotic minipumps. Two weeks later, rats from both groups were further randomized to receive either the mas receptor antagonist A-779 (0.5 mg/kg/day; n = 7 per group) or its vehicle (n = 7 per group) for the next 4 weeks. Blood pressure was monitored by telemetry, and circulating and tissue components of the renin-angiotensin system (RAS) were measured at the completion of the experiments. RESULTS Antihypertensive effects of olmesartan were associated with an increase in plasma renin concentration, plasma Ang I, Ang II, and Ang-(1-7), whereas serum aldosterone levels and kidney Ang II content were reduced. Preserved Ang-(1-7) content in kidneys was associated with increases of ACE2 protein but not activity and no changes on serum and kidney ACE activity. There was no change in cardiac peptide levels after olmesartan treatment. The antihypertensive effects of olmesartan were not altered by concomitant administration of the Ang-(1-7) receptor antagonist except for a mild further increase in plasma renin concentration. CONCLUSIONS Our study highlights the independent regulation of RAS among plasma, heart, and kidney tissue in response to AT(1)-R blockade. Ang-(1-7) through the mas receptor does not mediate long-term effects of olmesartan besides counterbalancing renin release in response to AT(1)-R blockade.
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Affiliation(s)
- Jasmina Varagic
- Hypertension and Vascular Research Center, Wake Forest University, Winston-Salem, NC, USA.
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Jiang T, Gao L, Guo J, Lu J, Wang Y, Zhang Y. Suppressing inflammation by inhibiting the NF-κB pathway contributes to the neuroprotective effect of angiotensin-(1-7) in rats with permanent cerebral ischaemia. Br J Pharmacol 2013; 167:1520-32. [PMID: 22817481 DOI: 10.1111/j.1476-5381.2012.02105.x] [Citation(s) in RCA: 121] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND AND PURPOSE Angiotensin-(1-7) [Ang-(1-7)] has anti-inflammatory effects in peripheral organs, but its effects in ischaemic stroke are unclear as yet. We investigated whether its anti-inflammatory effect contributes to the neuroprotection induced by Ang-(1-7) in a rat model of permanent middle cerebral artery occlusion (pMCAO). EXPERIMENTAL APPROACH We infused Ang-(1-7), Mas receptor antagonist A-779, angiotensin II type 2 receptor antagonist PD123319 or artificial CSF into the right lateral ventricle of male Sprague-Dawley rats from 48 h before onset of pMCAO until the rats were killed. Twenty-four hours after pMCAO, the neuroprotective effect of Ang-(1-7) was analysed by evaluating infarct volume and neurological deficits. The levels of oxidative stress were detected by spectrophotometric assay. The activation of NF-κB was assessed by Western blot and immunohistochemistry analysis. The level of COX-2 was tested by Western blot analysis and concentrations of pro-inflammatory cytokines were measured by elisa. KEY RESULTS Infusion of Ang-(1-7), i.c.v., significantly reduced infarct volume and improved neurological deficits. It decreased the levels of oxidative stress and suppressed NF-κB activity, which was accompanied by a reduction of pro-inflammatory cytokines and COX-2 in the peri-infarct regions. These effects of Ang-(1-7) were reversed by A-779 but not by PD123319. Additionally, infusion of A-779 alone increased oxidative stress levels and enhanced NF-κB activity, which was accompanied by an up-regulation of pro-inflammatory cytokines and COX-2. CONCLUSION AND IMPLICATIONS Our findings indicate that suppressing NF-κB dependent pathway via Mas receptor may represent one mechanism that contributes to the anti-inflammatory effects of Ang-(1-7) in rats with pMCAO.
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Affiliation(s)
- Teng Jiang
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
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Jiang T, Gao L, Zhu XC, Yu JT, Shi JQ, Tan MS, Lu J, Tan L, Zhang YD. Angiotensin-(1-7) inhibits autophagy in the brain of spontaneously hypertensive rats. Pharmacol Res 2013; 71:61-8. [PMID: 23499735 DOI: 10.1016/j.phrs.2013.03.001] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2013] [Revised: 03/05/2013] [Accepted: 03/06/2013] [Indexed: 12/19/2022]
Abstract
Autophagy is an important cellular process that mediates lysosomal degradation of damaged organelles, which is activated in response to a variety of stress-related diseases, including hypertension. The basal level of autophagy plays an important role in the maintenance of cellular homeostasis, whereas excessive autophagic activity leads to cell death and is considered as a contributing factor to several disorders. Recent works have demonstrated that Angiotensin-(1-7) [Ang-(1-7)] exerted its neuroprotective effects by modulating classic components of renin-angiotensin system associated with reducing oxidative stress and apoptosis in brains of spontaneously hypertensive rats (SHRs). However, the effect of Ang-(1-7) on autophagic activity in brain of hypertensive individual remains unclear. In this study, Wistar-Kyoto rats received intracerebroventricular (I.C.V.) infusion of artificial cerebrospinal fluid (aCSF) while SHRs received I.C.V. infusion of aCSF, Ang-(1-7), Mas receptor antagonist A-779, or angiotensin II type 2 receptor antagonist PD123319 for 4 weeks. Brain tissues were collected and analyzed by western blotting analysis, immunofluorescence assay, and transmission electron microscopic examination. Our study showed that infusion of Ang-(1-7) for 4 weeks inhibited the increase of microtubule-associated protein 1 light chain 3 (LC3)-II and Beclin-1 levels, as well as the autophagosome formation in SHR brain. Meanwhile, the reduction of p62 expression in SHR brain was also reversed by Ang-(1-7). Of note, the anti-autophagic effects of Ang-(1-7) were independent of blood pressure reduction and can be inhibited by A-779 and PD123319. These findings suggest that treatment with Ang-(1-7) may be useful to prevent hypertension-induced excessive autophagic activation in brain.
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Affiliation(s)
- Teng Jiang
- Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, China
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Zhang F, Ren J, Chan K, Chen H. Angiotensin-(1–7) regulates Angiotensin II-induced VCAM-1 expression on vascular endothelial cells. Biochem Biophys Res Commun 2013; 430:642-6. [DOI: 10.1016/j.bbrc.2012.11.098] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2012] [Accepted: 11/26/2012] [Indexed: 01/24/2023]
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El-Hashim AZ, Renno WM, Raghupathy R, Abduo HT, Akhtar S, Benter IF. Angiotensin-(1-7) inhibits allergic inflammation, via the MAS1 receptor, through suppression of ERK1/2- and NF-κB-dependent pathways. Br J Pharmacol 2012; 166:1964-76. [PMID: 22339213 DOI: 10.1111/j.1476-5381.2012.01905.x] [Citation(s) in RCA: 124] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND AND PURPOSE Angiotensin-(1-7) [Ang-(1-7)] has anti-inflammatory effects in models of cardiovascular disease and arthritis, but its effects in asthma are unknown. We investigated whether Ang-(1-7) has anti-inflammatory actions in a murine model of asthma. EXPERIMENTAL APPROACH The effects of Ang-(1-7) alone or in combination with the MAS1 receptor antagonist, A779, were evaluated over a 4 day period in an ovalbumin-challenged mouse model of allergic asthma. On day 5, bronchoalveolar lavage was performed, and lungs were sectioned and assessed histologically for quantification of goblet cells, perivascular and peribronchial inflammation and fibrosis. Biochemical analysis of the pro-inflammatory ERK1/2 and IκB-α was assessed. In addition, the effect of Ang-(1-7) on proliferation of human peripheral blood mononuclear cells (HPBMC) was investigated. KEY RESULTS Ang-(1-7) attenuated ovalbumin-induced increases in total cell counts, eosinophils, lymphocytes and neutrophils. Ang-(1-7) also decreased the ovalbumin-induced perivascular and peribronchial inflammation, fibrosis and goblet cell hyper/metaplasia. Additionally, Ang-(1-7) reduced the ovalbumin-induced increase in the phosphorylation of ERK1/2 and IκB-α. These effects of Ang-(1-7) were reversed by the MAS1 receptor antagonist A779. Furthermore, Ang-(1-7) inhibited phytohaemagglutinin (PHA)-induced HPBMC proliferation. CONCLUSION AND IMPLICATIONS Ang-(1-7), via its MAS1 receptor, acts as an anti-inflammatory pathway in allergic asthma, implying that activation of the MAS1 receptor may represent a novel approach to asthma therapy.
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Affiliation(s)
- Ahmed Z El-Hashim
- Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Kuwait.
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Jiang T, Gao L, Shi J, Lu J, Wang Y, Zhang Y. Angiotensin-(1-7) modulates renin-angiotensin system associated with reducing oxidative stress and attenuating neuronal apoptosis in the brain of hypertensive rats. Pharmacol Res 2012; 67:84-93. [PMID: 23127917 DOI: 10.1016/j.phrs.2012.10.014] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2012] [Revised: 10/25/2012] [Accepted: 10/25/2012] [Indexed: 11/28/2022]
Abstract
Angiotensin-(1-7) [Ang-(1-7)] has beneficial effects against hypertension-induced damage in heart and kidney, but its effects in brain are not clear as yet. The present study aimed to investigate the protective effects of Ang-(1-7) on the physiopathologic changes caused by hypertension in brain of spontaneously hypertensive rats (SHRs). Wistar-Kyoto rats received intracerebroventricular (I.C.V.) infusion of artificial cerebrospinal fluid (aCSF) while SHRs received I.C.V. infusion of Ang-(1-7), Mas receptor antagonist A-779 and aCSF for 4 weeks. Brain tissues were collected and analyzed by western blot, enzyme immunoassay, spectrophotometric assays and terminal deoxynucleotidyl transferase-mediated dUTP end-labeling (TUNEL) staining. Our study showed that infusion of Ang-(1-7) for 4 weeks significantly reduced the expression of Angiotensin II and Angiotensin II type 1 receptors in SHR brain. Additionally, it decreased the levels of malondialdehyde and elevated total superoxide dismutase activity, which was accompanied by reductions of NADPH oxidase subunit gp91(phox) and inducible nitric oxide synthase in the brain of SHR. The increases of the percentage of TUNEL-positive neurons and Bax to Bcl-2 ratio in SHR brain were also attenuated by Ang-(1-7). The anti-oxidative and anti-apoptosis effects of Ang-(1-7) are independent of blood pressure reduction and can be partially abolished by A-779. These findings suggest that chronic treatment with Ang-(1-7) is beneficial to attenuate hypertension-induced physiopathologic changes in brain and may be helpful to prevent hypertension-related cerebrovascular diseases.
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Affiliation(s)
- Teng Jiang
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, PR China
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Renno WM, Al-Banaw AG, George P, Abu-Ghefreh AA, Akhtar S, Benter IF. Angiotensin-(1-7) via the mas receptor alleviates the diabetes-induced decrease in GFAP and GAP-43 immunoreactivity with concomitant reduction in the COX-2 in hippocampal formation: an immunohistochemical study. Cell Mol Neurobiol 2012; 32:1323-36. [PMID: 22711212 PMCID: PMC11498388 DOI: 10.1007/s10571-012-9858-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2012] [Accepted: 06/05/2012] [Indexed: 12/23/2022]
Abstract
We have previously shown that chronic treatment with angiotensin-(1-7) [Ang-(1-7)] can prevent diabetes-induced cardiovascular dysfunction. However, effect of Ang-(1-7) treatment on diabetes-induced alterations in the CNS is unknown. The aim of this study was to test the hypothesis that treatment with Ang-(1-7) can produce protection against diabetes-induced CNS changes. We examined the effect of Ang-(1-7) on the number of cyclooxygenase-2 (COX-2) immunoreactive neurons and the glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes and assessed the changes in the neuronal growth-associated protein-43 (GAP-43) of the hippocampal formation in streptozotocin-induced diabetes in rats. Animals were sacrificed 30 days after induction of diabetes and/or treatment with Ang-(1-7). Ang-(1-7) treatment significantly prevented diabetes-induced decrease in the number of GFAP immunoreactive astrocytes and GAP-43 positive neurons in all hippocampal regions. Co-administration of A779, a selective Ang-(1-7) receptor antagonist, inhibited Ang-(1-7)-mediated protective effects indicating that Ang-(1-7) produces its effects through activation of receptor Mas. Further, Ang-(1-7) treatment through activation of Mas significantly prevented diabetes-induced increase in the number of the COX-2 immunolabeled neurons in all sub-regions of the hippocampus examined. These results show that Ang-(1-7) has a protective role against diabetes-induced changes in the CNS.
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Affiliation(s)
- Waleed M Renno
- Department of Anatomy, Faculty of Medicine, Kuwait University, P. O. Box 24923, Safat, 13110, Kuwait.
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Akhtar S, Yousif MHM, Dhaunsi GS, Chandrasekhar B, Al-Farsi O, Benter IF. Angiotensin-(1-7) inhibits epidermal growth factor receptor transactivation via a Mas receptor-dependent pathway. Br J Pharmacol 2012; 165:1390-400. [PMID: 21806601 DOI: 10.1111/j.1476-5381.2011.01613.x] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND AND PURPOSE The transactivation of the epidermal growth factor (EGF) receptor appears to be an important central transduction mechanism in mediating diabetes-induced vascular dysfunction. Angiotensin-(1-7) [Ang-(1-7)] via its Mas receptor can prevent the development of hyperglycaemia-induced cardiovascular complications. Here, we investigated whether Ang-(1-7) can inhibit hyperglycaemia-induced EGF receptor transactivation and its classical signalling via ERK1/2 and p38 MAPK in vivo and in vitro. EXPERIMENTAL APPROACH Streptozotocin-induced diabetic rats were chronically treated with Ang-(1-7) or AG1478, a selective EGF receptor inhibitor, for 4 weeks and mechanistic studies performed in the isolated mesenteric vasculature bed as well as in primary cultures of vascular smooth muscle cells (VSMCs). KEY RESULTS Diabetes significantly enhanced phosphorylation of EGF receptor at tyrosine residues Y992, Y1068, Y1086, Y1148, as well as ERK1/2 and p38 MAPK in the mesenteric vasculature bed whereas these changes were significantly attenuated upon Ang-(1-7) or AG1478 treatment. In VSMCs grown in conditions of high glucose (25 mM), an Src-dependent elevation in EGF receptor phosphorylation was observed. Ang-(1-7) inhibited both Ang II- and glucose-induced transactivation of EGF receptor. The inhibition of high glucose-mediated Src-dependant transactivation of EGF receptor by Ang-(1-7) could be prevented by a selective Mas receptor antagonist, D-Pro7-Ang-(1-7). CONCLUSIONS AND IMPLICATIONS These results show for the first time that Ang-(1-7) inhibits EGF receptor transactivation via a Mas receptor/Src-dependent pathway and might represent a novel general mechanism by which Ang-(1-7) exerts its beneficial effects in many disease states including diabetes-induced vascular dysfunction.
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Affiliation(s)
- Saghir Akhtar
- Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Safat, Kuwait.
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Giani JF, Burghi V, Veiras LC, Tomat A, Muñoz MC, Cao G, Turyn D, Toblli JE, Dominici FP. Angiotensin-(1–7) attenuates diabetic nephropathy in Zucker diabetic fatty rats. Am J Physiol Renal Physiol 2012; 302:F1606-15. [DOI: 10.1152/ajprenal.00063.2012] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Angiotensin (ANG)-(1–7) is known to attenuate diabetic nephropathy; however, its role in the modulation of renal inflammation and oxidative stress in type 2 diabetes is poorly understood. Thus in the present study we evaluated the renal effects of a chronic ANG-(1–7) treatment in Zucker diabetic fatty rats (ZDF), an animal model of type 2 diabetes and nephropathy. Sixteen-week-old male ZDF and their respective controls [lean Zucker rats (LZR)] were used for this study. The protocol involved three groups: 1) LZR + saline, 2) ZDF + saline, and 3) ZDF + ANG-(1–7). For 2 wk, animals were implanted with subcutaneous osmotic pumps that delivered either saline or ANG-(1–7) (100 ng·kg−1·min−1) ( n = 4). Renal fibrosis and tissue parameters of oxidative stress were determined. Also, renal levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), ED-1, hypoxia-inducible factor-1α (HIF-1α), and neutrophil gelatinase-associated lipocalin (NGAL) were determined by immunohistochemistry and immunoblotting. ANG-(1–7) induced a reduction in triglyceridemia, proteinuria, and systolic blood pressure (SBP) together with a restoration of creatinine clearance in ZDF. Additionally, ANG-(1–7) reduced renal fibrosis, decreased thiobarbituric acid-reactive substances, and restored the activity of both renal superoxide dismutase and catalase in ZDF. This attenuation of renal oxidative stress proceeded with decreased renal immunostaining of IL-6, TNF-α, ED-1, HIF-1α, and NGAL to values similar to those displayed by LZR. Angiotensin-converting enzyme type 2 (ACE2) and ANG II levels remained unchanged after treatment with ANG-(1–7). Chronic ANG-(1–7) treatment exerts a renoprotective effect in ZDF associated with a reduction of SBP, oxidative stress, and inflammatory markers. Thus ANG-(1–7) emerges as a novel target for treatment of diabetic nephropathy.
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Affiliation(s)
- Jorge F. Giani
- Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Valeria Burghi
- Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Luciana C. Veiras
- Facultad de Farmacia y Bioquímica, Cátedra de Fisiología, Universidad de Buenos Aires, Buenos Aires, Argentina; and
| | - Analía Tomat
- Facultad de Farmacia y Bioquímica, Cátedra de Fisiología, Universidad de Buenos Aires, Buenos Aires, Argentina; and
| | - Marina C. Muñoz
- Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Gabriel Cao
- Laboratory of Experimental Medicine, Hospital Alemán, Buenos Aires, Argentina
| | - Daniel Turyn
- Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Jorge E. Toblli
- Laboratory of Experimental Medicine, Hospital Alemán, Buenos Aires, Argentina
| | - Fernando P. Dominici
- Facultad de Farmacia y Bioquímica, Instituto de Química y Fisicoquímica Biológicas, Universidad de Buenos Aires, Buenos Aires, Argentina
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