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Tiwari P, Elgazzaz M, Lazartigues E, Hanif K. Effect of Diminazene Aceturate, an ACE2 activator, on platelet CD40L signaling induced glial activation in rat model of hypertension. Int Immunopharmacol 2024; 139:112654. [PMID: 38996777 DOI: 10.1016/j.intimp.2024.112654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 06/30/2024] [Accepted: 07/06/2024] [Indexed: 07/14/2024]
Abstract
Hypertension causes platelet activation and adhesion in the brain resulting in glial activation and neuroinflammation. Further, activation of Angiotensin-Converting Enzyme 2/Angiotensin (1-7)/Mas Receptor (ACE2/Ang (1-7)/MasR) axis of central Renin-Angiotensin System (RAS), is known to reduce glial activation and neuroinflammation, thereby exhibiting anti-hypertensive and anti-neuroinflammatory properties. Therefore, in the present study, the role of ACE2/Ang (1-7)/MasR axis was studied on platelet-induced glial activation and neuroinflammation using Diminazene Aceturate (DIZE), an ACE2 activator, in astrocytes and microglial cells as well as in rat model of hypertension. We found that the ACE2 activator DIZE, independently of its BP-lowering properties, efficiently prevented hypertension-induced glial activation, neuroinflammation, and platelet CD40-CD40L signaling via upregulation of ACE2/Ang (1-7)/MasR axis. Further, DIZE decreased platelet deposition in the brain by reducing the expression of adhesion molecules on the brain endothelium. Activation of ACE2 also reduced hypertension-induced endothelial dysfunction by increasing eNOS bioavailability. Interestingly, platelets isolated from hypertensive rats or activated with ADP had significantly increased sCD40L levels and induced significantly more glial activation than platelets from DIZE treated group. Therefore, injection of DIZE pre-treated ADP-activated platelets into normotensive rats strongly reduced glial activation compared to ADP-treated platelets. Moreover, CD40L-induced glial activation, CD40 expression, and NFкB-NLRP3 inflammatory signaling are reversed by DIZE. Furthermore, the beneficial effects of ACE2 activation, DIZE was found to be significantly blocked by MLN4760 (ACE2 inhibitor) as well as A779 (MasR antagonist) treatments. Hence, our study demonstrated that ACE2 activation reduced the platelet CD40-CD40L induced glial activation and neuroinflammation, hence imparted neuroprotection.
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Affiliation(s)
- Priya Tiwari
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Mona Elgazzaz
- Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Eric Lazartigues
- Department of Pharmacology & Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
| | - Kashif Hanif
- Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow 226031, U.P., India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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Semenikhina M, Bohovyk R, Fedoriuk M, Stefanenko M, Klemens CA, Oates JC, Staruschenko A, Palygin O. Renin-angiotensin system-mediated nitric oxide signaling in podocytes. Am J Physiol Renal Physiol 2024; 327:F532-F542. [PMID: 39024356 PMCID: PMC11460333 DOI: 10.1152/ajprenal.00316.2023] [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: 10/09/2023] [Revised: 07/10/2024] [Accepted: 07/10/2024] [Indexed: 07/20/2024] Open
Abstract
Nitric oxide (NO) is widely recognized for its role in regulating renal function and blood pressure. However, the precise mechanisms by which NO affects renal epithelial cells remain understudied. Our previous research has shown that NO signaling in glomerular podocytes can be initiated by Angiotensin II (ANG II) but not by ATP. This study aims to elucidate the crucial interplay between the renin-angiotensin system (RAS) and NO production in podocytes. To conduct our research, we used cultured human podocytes and freshly isolated rat glomeruli. A variety of RAS peptides were used, alongside confocal microscopy, to detect NO production and NO/Ca2+ cross talk. Dynamic changes in the podocyte cytoskeleton, mediated by RAS-NO intracellular signaling, were observed using fluorescent labeling for F-actin and scanning probe microscopy. The experiments demonstrated that ANG II and ANG III generated high levels of NO by activating the angiotensin II type 2 receptor (AT2R). We did not detect functional MAS receptor presence in podocytes, and the moderate NO response to ANG 1-7 was also mediated through AT2R. Furthermore, NO production impacted intracellular Ca2+ signaling and correlated with an increase in podocyte volume and growth. Scanning probe experiments revealed that AT2R activation and the corresponding NO generation are responsible for the protrusion of podocyte lamellipodia. Taken together, our data indicate that AT2R activation enhances NO production in podocytes and subsequently mediates changes in Ca2+ signaling and podocyte volume dynamics. These mechanisms may play a significant role in both physiological and pathophysiological interactions between the RAS and podocytes.NEW & NOTEWORTHY The renin-angiotensin system plays a crucial role in the production of intracellular nitric oxide within podocytes. This mechanism operates through the activation of the angiotensin II type 2 receptor, leading to dynamic modifications in intracellular calcium levels and the actin filament network. This intricate process is vital for linking the activity of angiotensin receptors to podocyte function.
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Affiliation(s)
- Marharyta Semenikhina
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States
| | - Ruslan Bohovyk
- Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida, United States
| | - Mykhailo Fedoriuk
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States
| | - Mariia Stefanenko
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States
| | - Christine A Klemens
- Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida, United States
- Hypertension and Kidney Research Center, University of South Florida, Tampa, Florida, United States
| | - Jim C Oates
- Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina, United States
| | - Alexander Staruschenko
- Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida, United States
- Hypertension and Kidney Research Center, University of South Florida, Tampa, Florida, United States
- James A. Haley Veterans' Hospital, Tampa, Florida, United States
| | - Oleg Palygin
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States
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Villacampa A, Shamoon L, Valencia I, Morales C, Figueiras S, de la Cuesta F, Sánchez-Niño D, Díaz-Araya G, Sánchez-Pérez I, Lorenzo Ó, Sánchez-Ferrer CF, Peiró C. SARS-CoV-2 S Protein Reduces Cytoprotective Defenses and Promotes Human Endothelial Cell Senescence. Aging Dis 2024:AD.2024.0405. [PMID: 39012668 DOI: 10.14336/ad.2024.0405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 06/25/2024] [Indexed: 07/17/2024] Open
Abstract
Premature vascular aging and endothelial cell senescence are major risk factors for cardiovascular diseases and atherothrombotic disturbances, which are main complications of both acute and long COVID-19. The S protein of SARS-CoV2, which acts as the receptor binding protein for the viral infection, is able to induce endothelial cells inflammation and it has been found as an isolated element in the circulation and in human tissues reservoirs months after infection. Here, we investigated whether the S protein is able to directly induce endothelial cell senescence and deciphered some of the mechanisms involved. In primary cultures of human umbilical vein endothelial cells (HUVEC), SARS-CoV-2 S protein enhanced in a concentration-dependent manner the cellular content of senescence and DNA damage response markers (senescence-associated-β galactosidase, γH2AX), as well as growth-arrest effectors (p53, p21, p16). In parallel, the S protein reduced the availability of cytoprotective proteins, such as the anti-aging protein klotho, Nrf2 or heme oxygenase-1, and caused functional harm by impairing ex vivo endothelial-dependent vasorelaxation in murine microvessels. These effects were prevented by the pharmacological inhibition of the NLRP3 inflammasome with MCC950. Furthermore, the supplementation with either recombinant klotho or angiotensin-(1-7), equally protected against the pro-senescence, pro-inflammatory and pro-oxidant action of the S protein. Globally, this study proposes novel mechanisms of disease in the context of COVID-19 and its vascular sequelae and provides pharmacological clues in order to prevent such complications.
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Affiliation(s)
- Alicia Villacampa
- Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, Spain
- Vascular Pharmacology and Metabolism (FARMAVASM) group, IdiPAZ, Madrid, Spain
| | - Licia Shamoon
- Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, Spain
- Vascular Pharmacology and Metabolism (FARMAVASM) group, IdiPAZ, Madrid, Spain
| | - Inés Valencia
- Molecular Neuroinflammation and Neuronal Plasticity Research Laboratory, Hospital Universitario Santa Cristina, IIS Hospital Universitario de La Princesa, Madrid, Spain
| | - Cristina Morales
- Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, Spain
| | - Sofía Figueiras
- Department of Biochemistry, School of Medicine, Universidad Autónoma de Madrid, Spain
| | - Fernando de la Cuesta
- Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, Spain
- Vascular Pharmacology and Metabolism (FARMAVASM) group, IdiPAZ, Madrid, Spain
| | - Dolores Sánchez-Niño
- Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, Spain
- Nephrology and Hypertension Lab, IIS-Fundación Jimenez Diaz, Madrid, Spain
| | - Guillermo Díaz-Araya
- Department of Pharmacological &;amp Toxicological Chemistry, Faculty of Chemical &;amp Pharmaceutical Sciences &;amp Faculty of Medicine, University of Chile, Santiago, Chile
| | - Isabel Sánchez-Pérez
- Department of Biochemistry, School of Medicine, Universidad Autónoma de Madrid, Spain
- Instituto de Investigaciones Biomédicas "Sols-Morreale" IIBM-CSIC-UAM, Madrid, Spain
- Biomarkers and Personalized Approach to Cancer (BioPAC) Group. Area 3 Cancer -Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
- Biomedical Research Networking Centre on Rare Diseases, CIBERER, ISCIII, Madrid, Spain
| | - Óscar Lorenzo
- Department of Medicine, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
- Laboratory of Diabetes and Vascular pathology, IIS-Fundación Jiménez Díaz, Madrid, Spain
- Biomedical Research Networking Centre on Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - Carlos Félix Sánchez-Ferrer
- Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, Spain
- Vascular Pharmacology and Metabolism (FARMAVASM) group, IdiPAZ, Madrid, Spain
| | - Concepción Peiró
- Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, Spain
- Vascular Pharmacology and Metabolism (FARMAVASM) group, IdiPAZ, Madrid, Spain
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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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Molaei A, Molaei E, Hayes AW, Karimi G. Mas receptor: a potential strategy in the management of ischemic cardiovascular diseases. Cell Cycle 2023; 22:1654-1674. [PMID: 37365840 PMCID: PMC10361149 DOI: 10.1080/15384101.2023.2228089] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 05/10/2023] [Accepted: 06/16/2023] [Indexed: 06/28/2023] Open
Abstract
MasR is a critical element in the RAS accessory pathway that protects the heart against myocardial infarction, ischemia-reperfusion injury, and pathological remodeling by counteracting the effects of AT1R. This receptor is mainly stimulated by Ang 1-7, which is a bioactive metabolite of the angiotensin produced by ACE2. MasR activation attenuates ischemia-related myocardial damage by facilitating vasorelaxation, improving cell metabolism, reducing inflammation and oxidative stress, inhibiting thrombosis, and stabilizing atherosclerotic plaque. It also prevents pathological cardiac remodeling by suppressing hypertrophy- and fibrosis-inducing signals. In addition, the potential of MasR in lowering blood pressure, improving blood glucose and lipid profiles, and weight loss has made it effective in modulating risk factors for coronary artery disease including hypertension, diabetes, dyslipidemia, and obesity. Considering these properties, the administration of MasR agonists offers a promising approach to the prevention and treatment of ischemic heart disease.Abbreviations: Acetylcholine (Ach); AMP-activated protein kinase (AMPK); Angiotensin (Ang); Angiotensin receptor (ATR); Angiotensin receptor blocker (ARB); Angiotensin-converting enzyme (ACE); Angiotensin-converting enzyme inhibitor (ACEI); Anti-PRD1-BF1-RIZ1 homologous domain containing 16 (PRDM16); bradykinin (BK); Calcineurin (CaN); cAMP-response element binding protein (CREB); Catalase (CAT); C-C Motif Chemokine Ligand 2 (CCL2); Chloride channel 3 (CIC3); c-Jun N-terminal kinases (JNK); Cluster of differentiation 36 (CD36); Cocaine- and amphetamine-regulated transcript (CART); Connective tissue growth factor (CTGF); Coronary artery disease (CAD); Creatine phosphokinase (CPK); C-X-C motif chemokine ligand 10 (CXCL10); Cystic fibrosis transmembrane conductance regulator (CFTR); Endothelial nitric oxide synthase (eNOS); Extracellular signal-regulated kinase 1/2 (ERK 1/2); Fatty acid transport protein (FATP); Fibroblast growth factor 21 (FGF21); Forkhead box protein O1 (FoxO1); Glucokinase (Gk); Glucose transporter (GLUT); Glycogen synthase kinase 3β (GSK3β); High density lipoprotein (HDL); High sensitive C-reactive protein (hs-CRP); Inositol trisphosphate (IP3); Interleukin (IL); Ischemic heart disease (IHD); Janus kinase (JAK); Kruppel-like factor 4 (KLF4); Lactate dehydrogenase (LDH); Left ventricular end-diastolic pressure (LVEDP); Left ventricular end-systolic pressure (LVESP); Lipoprotein lipase (LPL); L-NG-Nitro arginine methyl ester (L-NAME); Low density lipoprotein (LDL); Mammalian target of rapamycin (mTOR); Mas-related G protein-coupled receptors (Mrgpr); Matrix metalloproteinase (MMP); MAPK phosphatase-1 (MKP-1); Mitogen-activated protein kinase (MAPK); Monocyte chemoattractant protein-1 (MCP-1); NADPH oxidase (NOX); Neuropeptide FF (NPFF); Neutral endopeptidase (NEP); Nitric oxide (NO); Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB); Nuclear-factor of activated T-cells (NFAT); Pancreatic and duodenal homeobox 1 (Pdx1); Peroxisome proliferator- activated receptor γ (PPARγ); Phosphoinositide 3-kinases (PI3k); Phospholipase C (PLC); Prepro-orexin (PPO); Prolyl-endopeptidase (PEP); Prostacyclin (PGI2); Protein kinase B (Akt); Reactive oxygen species (ROS); Renin-angiotensin system (RAS); Rho-associated protein kinase (ROCK); Serum amyloid A (SAA); Signal transducer and activator of transcription (STAT); Sirtuin 1 (Sirt1); Slit guidance ligand 3 (Slit3); Smooth muscle 22α (SM22α); Sterol regulatory element-binding protein 1 (SREBP-1c); Stromal-derived factor-1a (SDF); Superoxide dismutase (SOD); Thiobarbituric acid reactive substances (TBARS); Tissue factor (TF); Toll-like receptor 4 (TLR4); Transforming growth factor β1 (TGF-β1); Tumor necrosis factor α (TNF-α); Uncoupling protein 1 (UCP1); Ventrolateral medulla (VLM).
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Affiliation(s)
- Ali Molaei
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Emad Molaei
- PharmD, Assistant of Clinical Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - A. Wallace Hayes
- University of South Florida College of Public Health, Tampa, Florida, USA
| | - Gholamreza Karimi
- Pharmaceutical Research Center, Institute of Pharmaceutical Technology, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmacodynamics and Toxicology, Faculty of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Tiwari P, Tiwari V, Gupta S, Shukla S, Hanif K. Activation of Angiotensin-converting Enzyme 2 Protects Against Lipopolysaccharide-induced Glial Activation by Modulating Angiotensin-converting Enzyme 2/Angiotensin (1-7)/Mas Receptor Axis. Mol Neurobiol 2023; 60:203-227. [PMID: 36251234 DOI: 10.1007/s12035-022-03061-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 10/03/2022] [Indexed: 12/30/2022]
Abstract
Neuroinflammation is associated with activation of glial cells and pro-inflammatory arm of the central Renin Angiotensin System (RAS) namely, Angiotensin-Converting Enzyme/Angiotensin II/Angiotensin Type 1 Receptor (ACE/Ang II/AT1R) axis. Apart from this, another axis of RAS also exists, Angiotensin-Converting Enzyme 2/Angiotensin (1-7)/Mas Receptor (ACE2/Ang (1-7)/MasR), which counters ACE/Ang II/AT1R axis by showing anti-inflammatory properties. However, the role of ACE2/Ang (1-7)/MasR axis has not been explored in glial activation and neuroinflammation. Hence, the present study tries to unveil the role of ACE2/Ang (1-7)/MasR axis in lipopolysaccharide (LPS)-induced neuroinflammation using diminazene aceturate (DIZE), an ACE2 activator, in astroglial (C6) and microglial (BV2) cells as well as male SD rats. We found that ACE2 activation efficiently prevented LPS-induced changes by decreasing glial activation, inflammatory signaling, cell migration, ROS generation via upregulation of ACE2/Ang (1-7)/MasR signaling. In addition, activation of ACE2/Ang (1-7)/MasR axis by DIZE significantly suppressed the pro-inflammatory ACE/Ang II/AT1R axis by reducing Ang II level in neuroinflammatory conditions induced by LPS in both in vitro and in vivo. ACE2/Ang (1-7)/MasR axis activation further decreased mitochondrial depolarization and apoptosis, hence providing neuroprotection. Furthermore, to validate that the beneficial effect of the ACE2 activator was indeed through MasR, a selective MasR antagonist (A779) was used that significantly blocked the anti-inflammatory effect of ACE2 activation by DIZE. Hence, our study demonstrated that ACE2 activation imparted neuroprotection by enhancing ACE2/Ang (1-7)/MasR signaling which in turn decreased glial activation, neuroinflammation, and apoptosis and improved mitochondrial health.
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Affiliation(s)
- Priya Tiwari
- Division of Pharmacology, CSIR- Central Drug Research Institute, Lucknow-226031, Uttar Pradesh, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India
| | - Virendra Tiwari
- Division of Neuroscience and Ageing Biology, CSIR- Central Drug Research Institute, Lucknow-226031, Uttar Pradesh, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India
| | - Shivangi Gupta
- Division of Neuroscience and Ageing Biology, CSIR- Central Drug Research Institute, Lucknow-226031, Uttar Pradesh, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India
| | - Shubha Shukla
- Division of Neuroscience and Ageing Biology, CSIR- Central Drug Research Institute, Lucknow-226031, Uttar Pradesh, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India
| | - Kashif Hanif
- Division of Pharmacology, CSIR- Central Drug Research Institute, Lucknow-226031, Uttar Pradesh, India. .,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India.
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Ranjbar T, Oza PP, Kashfi K. The Renin-Angiotensin-Aldosterone System, Nitric Oxide, and Hydrogen Sulfide at the Crossroads of Hypertension and COVID-19: Racial Disparities and Outcomes. Int J Mol Sci 2022; 23:ijms232213895. [PMID: 36430371 PMCID: PMC9699619 DOI: 10.3390/ijms232213895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 11/07/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022] Open
Abstract
Coronavirus disease 2019 is caused by SARS-CoV-2 and is more severe in the elderly, racial minorities, and those with comorbidities such as hypertension and diabetes. These pathologies are often controlled with medications involving the renin-angiotensin-aldosterone system (RAAS). RAAS is an endocrine system involved in maintaining blood pressure and blood volume through components of the system. SARS-CoV-2 enters the cells through ACE2, a membrane-bound protein related to RAAS. Therefore, the use of RAAS inhibitors could worsen the severity of COVID-19's symptoms, especially amongst those with pre-existing comorbidities. Although a vaccine is currently available to prevent and reduce the symptom severity of COVID-19, other options, such as nitric oxide and hydrogen sulfide, may also have utility to prevent and treat this virus.
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Affiliation(s)
- Tara Ranjbar
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY 10031, USA
| | - Palak P. Oza
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY 10031, USA
| | - Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY 10031, USA
- Graduate Program in Biology, City University of New York Graduate Center, New York, NY 10016, USA
- Correspondence:
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8
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da Silva MC, dos Santos VM, da Silva MVB, Prazeres TCMM, Cartágenes MDSS, Calzerra NTM, de Queiroz TM. Involvement of shedding induced by ADAM17 on the nitric oxide pathway in hypertension. Front Mol Biosci 2022; 9:1032177. [PMID: 36310604 PMCID: PMC9614329 DOI: 10.3389/fmolb.2022.1032177] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 10/04/2022] [Indexed: 11/15/2022] Open
Abstract
A Disintegrin and Metalloprotease 17 (ADAM17), also called tumor necrosis factor-ɑ (TNF-ɑ) convertase (TACE), is a well-known protease involved in the sheddase of growth factors, chemokines and cytokines. ADAM17 is also enrolled in hypertension, especially by shedding of angiotensin converting enzyme type 2 (ACE2) leading to impairment of angiotensin 1–7 [Ang-(1–7)] production and injury in vasodilation, induction of renal damage and cardiac hypertrophy. Activation of Mas receptor (MasR) by binding of Ang-(1–7) induces an increase in the nitric oxide (NO) gaseous molecule, which is an essential factor of vascular homeostasis and blood pressure control. On the other hand, TNF-ɑ has demonstrated to stimulate a decrease in nitric oxide bioavailability, triggering a disrupt in endothelium-dependent vasorelaxation. In spite of the previous studies, little knowledge is available about the involvement of the metalloprotease 17 and the NO pathways. Here we will provide an overview of the role of ADAM17 and Its mechanisms implicated with the NO formation.
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Affiliation(s)
- Mirelly Cunha da Silva
- Laboratory of Nutrition, Physical Activity and Phenotypic Plasticity, Federal University of Pernambuco, Vitória de Santo Antão, Brazil
| | - Vanessa Maria dos Santos
- Laboratory of Nutrition, Physical Activity and Phenotypic Plasticity, Federal University of Pernambuco, Vitória de Santo Antão, Brazil
| | - Matheus Vinícius B. da Silva
- Laboratory of Nutrition, Physical Activity and Phenotypic Plasticity, Federal University of Pernambuco, Vitória de Santo Antão, Brazil
| | | | | | | | - Thyago Moreira de Queiroz
- Laboratory of Nutrition, Physical Activity and Phenotypic Plasticity, Federal University of Pernambuco, Vitória de Santo Antão, Brazil
- *Correspondence: Thyago Moreira de Queiroz,
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9
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Pelle MC, Zaffina I, Lucà S, Forte V, Trapanese V, Melina M, Giofrè F, Arturi F. Endothelial Dysfunction in COVID-19: Potential Mechanisms and Possible Therapeutic Options. Life (Basel) 2022; 12:1605. [PMID: 36295042 PMCID: PMC9604693 DOI: 10.3390/life12101605] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 09/29/2022] [Accepted: 10/12/2022] [Indexed: 11/06/2022] Open
Abstract
SARS-CoV-2, a novel coronavirus found in Wuhan (China) at the end of 2019, is the etiological agent of the current pandemic that is a heterogeneous disease, named coronavirus disease 2019 (COVID-19). SARS-CoV-2 affects primarily the lungs, but it can induce multi-organ involvement such as acute myocardial injury, myocarditis, thromboembolic eventsandrenal failure. Hypertension, chronic kidney disease, diabetes mellitus and obesity increase the risk of severe complications of COVID-19. There is no certain explanation for this systemic COVID-19 involvement, but it could be related to endothelial dysfunction, due to direct (endothelial cells are infected by the virus) and indirect damage (systemic inflammation) factors. Angiotensin-converting enzyme 2 (ACE2), expressed in human endothelium, has a fundamental role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In fact, ACE2 is used as a receptor by SARS-CoV-2, leading to the downregulation of these receptors on endothelial cells; once inside, this virus reduces the integrity of endothelial tissue, with exposure of prothrombotic molecules, platelet adhesion, activation of coagulation cascades and, consequently, vascular damage. Systemic microangiopathy and thromboembolism can lead to multi-organ failure with an elevated risk of death. Considering the crucial role of the immunological response and endothelial damage in developing the severe form of COVID-19, in this review, we will attempt to clarify the underlying pathophysiological mechanisms.
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Affiliation(s)
- Maria Chiara Pelle
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
| | - Isabella Zaffina
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
| | - Stefania Lucà
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
| | - Valentina Forte
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
| | - Vincenzo Trapanese
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
| | - Melania Melina
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
| | - Federica Giofrè
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
| | - Franco Arturi
- Unit of Internal Medicine, Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
- Research Centre for the Prevention and Treatment of Metabolic Diseases (CR METDIS), University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
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10
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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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Lin H, Geurts F, Hassler L, Batlle D, Mirabito Colafella KM, Denton KM, Zhuo JL, Li XC, Ramkumar N, Koizumi M, Matsusaka T, Nishiyama A, Hoogduijn MJ, Hoorn EJ, Danser AHJ. Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting. Pharmacol Rev 2022; 74:462-505. [PMID: 35710133 PMCID: PMC9553117 DOI: 10.1124/pharmrev.120.000236] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The concept of local formation of angiotensin II in the kidney has changed over the last 10-15 years. Local synthesis of angiotensinogen in the proximal tubule has been proposed, combined with prorenin synthesis in the collecting duct. Binding of prorenin via the so-called (pro)renin receptor has been introduced, as well as megalin-mediated uptake of filtered plasma-derived renin-angiotensin system (RAS) components. Moreover, angiotensin metabolites other than angiotensin II [notably angiotensin-(1-7)] exist, and angiotensins exert their effects via three different receptors, of which angiotensin II type 2 and Mas receptors are considered renoprotective, possibly in a sex-specific manner, whereas angiotensin II type 1 (AT1) receptors are believed to be deleterious. Additionally, internalized angiotensin II may stimulate intracellular receptors. Angiotensin-converting enzyme 2 (ACE2) not only generates angiotensin-(1-7) but also acts as coronavirus receptor. Multiple, if not all, cardiovascular diseases involve the kidney RAS, with renal AT1 receptors often being claimed to exert a crucial role. Urinary RAS component levels, depending on filtration, reabsorption, and local release, are believed to reflect renal RAS activity. Finally, both existing drugs (RAS inhibitors, cyclooxygenase inhibitors) and novel drugs (angiotensin receptor/neprilysin inhibitors, sodium-glucose cotransporter-2 inhibitors, soluble ACE2) affect renal angiotensin formation, thereby displaying cardiovascular efficacy. Particular in the case of the latter three, an important question is to what degree they induce renoprotection (e.g., in a renal RAS-dependent manner). This review provides a unifying view, explaining not only how kidney angiotensin formation occurs and how it is affected by drugs but also why drugs are renoprotective when altering the renal RAS. SIGNIFICANCE STATEMENT: Angiotensin formation in the kidney is widely accepted but little understood, and multiple, often contrasting concepts have been put forward over the last two decades. This paper offers a unifying view, simultaneously explaining how existing and novel drugs exert renoprotection by interfering with kidney angiotensin formation.
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Affiliation(s)
- Hui Lin
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Frank Geurts
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Luise Hassler
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Daniel Batlle
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Katrina M Mirabito Colafella
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Kate M Denton
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Jia L Zhuo
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Xiao C Li
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Nirupama Ramkumar
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Masahiro Koizumi
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Taiji Matsusaka
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Akira Nishiyama
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Martin J Hoogduijn
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - Ewout J Hoorn
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
| | - A H Jan Danser
- Division of Pharmacology and Vascular Medicine (H.L., A.H.J.D.) and Division of Nephrology and Transplantation (F.G., M.J.H., E.J.H.), Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands; Northwestern University Feinberg School of Medicine, Chicago, Illinois (L.H., D.B.); Monash University, Melbourne, Australia (K.M.M.C., K.M.D.); Tulane University School of Medicine, New Orleans, Louisiana (J.L.Z., X.C.L.); Division of Nephrology and Hypertension, University of Utah School of Medicine, Salt Lake City, Utah (N.R.); Division of Nephrology, Endocrinology, and Metabolism (M.K.) and Institute of Medical Sciences and Department of Basic Medicine (M.K., T.M.), Tokai University School of Medicine, Isehara, Japan; and Department of Pharmacology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan (A.N.)
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12
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Barzegar M, Stokes KY, Chernyshev O, Kelley RE, Alexander JS. The Role of the ACE2/MasR Axis in Ischemic Stroke: New Insights for Therapy. Biomedicines 2021; 9:1667. [PMID: 34829896 PMCID: PMC8615891 DOI: 10.3390/biomedicines9111667] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 11/02/2021] [Accepted: 11/08/2021] [Indexed: 12/15/2022] Open
Abstract
Ischemic stroke remains the leading cause of neurologically based morbidity and mortality. Current stroke treatment is limited to two classes of FDA-approved drugs: thrombolytic agents (tissue plasminogen activator (tPA)) and antithrombotic agents (aspirin and heparin), which have a narrow time-window (<4.5 h) for administration after onset of stroke symptoms. While thrombolytic agents restore perfusion, they carry serious risks for hemorrhage, and do not influence damage responses during reperfusion. Consequently, stroke therapies that can suppress deleterious effects of ischemic injury are desperately needed. Angiotensin converting enzyme-2 (ACE2) has been recently suggested to beneficially influence experimental stroke outcomes by converting the vasoconstrictor Ang II into the vasodilator Ang 1-7. In this review, we extensively discuss the protective functions of ACE2-Ang (1-7)-MasR axis of renin angiotensin system (RAS) in ischemic stroke.
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Affiliation(s)
- Mansoureh Barzegar
- Molecular and Cellular Physiology, Ochsner-LSU Health Sciences Center, Shreveport, LA 71130-3932, USA; (M.B.); (K.Y.S.)
| | - Karen Y. Stokes
- Molecular and Cellular Physiology, Ochsner-LSU Health Sciences Center, Shreveport, LA 71130-3932, USA; (M.B.); (K.Y.S.)
| | - Oleg Chernyshev
- Neurology, Ochsner-LSU Health Sciences Center, Shreveport, LA 71130-3932, USA; (O.C.); (R.E.K.)
| | - Roger E. Kelley
- Neurology, Ochsner-LSU Health Sciences Center, Shreveport, LA 71130-3932, USA; (O.C.); (R.E.K.)
| | - Jonathan S. Alexander
- Molecular and Cellular Physiology, Ochsner-LSU Health Sciences Center, Shreveport, LA 71130-3932, USA; (M.B.); (K.Y.S.)
- Neurology, Ochsner-LSU Health Sciences Center, Shreveport, LA 71130-3932, USA; (O.C.); (R.E.K.)
- Medicine, LSU Health Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA
- Oral and Maxillofacial Surgery, Ochsner-LSU Health Sciences Center, Shreveport, LA 71130-3932, USA
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13
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Ionescu M, Stoian AP, Rizzo M, Serban D, Nuzzo D, Mazilu L, Suceveanu AI, Dascalu AM, Parepa IR. The Role of Endothelium in COVID-19. Int J Mol Sci 2021; 22:11920. [PMID: 34769350 PMCID: PMC8584762 DOI: 10.3390/ijms222111920] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 10/27/2021] [Accepted: 10/31/2021] [Indexed: 01/08/2023] Open
Abstract
The 2019 novel coronavirus, known as severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) or coronavirus disease 2019 (COVID-19), is causing a global pandemic. The virus primarily affects the upper and lower respiratory tracts and raises the risk of a variety of non-pulmonary consequences, the most severe and possibly fatal of which are cardiovascular problems. Data show that almost one-third of the patients with a moderate or severe form of COVID-19 had preexisting cardiovascular comorbidities such as diabetes mellitus, obesity, hypertension, heart failure, or coronary artery disease. SARS-CoV2 causes hyper inflammation, hypoxia, apoptosis, and a renin-angiotensin system imbalance in a variety of cell types, primarily endothelial cells. Profound endothelial dysfunction associated with COVID-19 can be the cause of impaired organ perfusion that may generate acute myocardial injury, renal failure, and a procoagulant state resulting in thromboembolic events. We discuss the most recent results on the involvement of endothelial dysfunction in the pathogenesis of COVID-19 in patients with cardiometabolic diseases in this review. We also provide insights on treatments that may reduce the severity of this viral infection.
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Affiliation(s)
- Mihaela Ionescu
- Cardiology Department, Faculty of Medicine, Ovidius University of Constanţa, 900527 Constanţa, Romania; (M.I.); (I.R.P.)
| | - Anca Pantea Stoian
- Diabetes, Nutrition, and Metabolic Diseases Department, Faculty of Medicine, Carol Davila University, 050474 Bucharest, Romania; (A.P.S.); (M.R.)
| | - Manfredi Rizzo
- Diabetes, Nutrition, and Metabolic Diseases Department, Faculty of Medicine, Carol Davila University, 050474 Bucharest, Romania; (A.P.S.); (M.R.)
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, 90100 Palermo, Italy
| | - Dragos Serban
- Forth Surgery Department, Emergency University Hospital Bucharest and Faculty of Medicine, Carol Davila University, 050474 Bucharest, Romania;
| | - Domenico Nuzzo
- Italian National Research Council, Institute for Research and Biomedical Innovation (CNR-IRIB), 90100 Palermo, Italy
| | - Laura Mazilu
- Oncology Department, Faculty of Medicine, Ovidius University of Constanţa, 900527 Constanţa, Romania;
| | - Andra Iulia Suceveanu
- Internal Medicine Department, Faculty of Medicine, Ovidius University of Constanţa, 900527 Constanţa, Romania;
| | - Ana Maria Dascalu
- Department of Ophthalmology, Emergency University Hospital Bucharest and Faculty of Medicine, Carol Davila University, 050474 Bucharest, Romania;
| | - Irinel Raluca Parepa
- Cardiology Department, Faculty of Medicine, Ovidius University of Constanţa, 900527 Constanţa, Romania; (M.I.); (I.R.P.)
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Barzegar M, Vital S, Stokes KY, Wang Y, Yun JW, White LA, Chernyshev O, Kelley RE, Alexander JS. Human placenta mesenchymal stem cell protection in ischemic stroke is angiotensin converting enzyme-2 and masR receptor-dependent. STEM CELLS (DAYTON, OHIO) 2021; 39:1335-1348. [PMID: 34124808 PMCID: PMC8881785 DOI: 10.1002/stem.3426] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 04/29/2021] [Indexed: 12/15/2022]
Abstract
Thromboembolic stroke remains a major cause of neurological disability and death. Current stroke treatments (aspirin, tissue plasminogen activator) are significantly limited by timing and risks for hemorrhage which have driven researchers to explore other approaches. Stem cell‐based therapy appears to be an effective option for ischemic stroke. Besides trans‐differentiation into neural cells, stem cells also provide acute protection via paracrine signaling pathways through which releasing neuroprotective factors. We previously reported that intraperitoneal administration of human placenta mesenchymal stem cell (hPMSC) therapy upon reperfusion significantly protected the brain against middle cerebral artery occlusion (MCAO)‐induced injury. In the present study, we specifically investigated the role of hPMSC‐derived angiotensin converting enzyme‐2 (ACE‐2) in protection of MCAO‐induced brain injury by measurement of brain tissue viability, cerebral blood flow, and neurological score. Here, we report for the first time that hPMSC expressing substantial amount of ACE‐2, which mediates hPMSC protection in the MCAO model. Strikingly, we found that the protective effects of hPMSC in MCAO‐induced brain injury could be attenuated by pretreatment of hPMSCs with MLN‐4760, a specific inhibitor of ACE‐2 activity, or by transfection of hPMSCs with ACE‐2‐shRNA‐lentivirus. The hPMSC‐derived ACE‐2 specific protective mechanism was further demonstrated by administration of PD123319, an Angiotensin type‐2 receptor antagonist, or A779, a MasR antagonist. Importantly, our study demonstrated that the protective effects of hPMSC in experimental stroke are ACE‐2/MasR dependent and this signaling pathway represents an innovative and highly promising approach for targeted stroke therapy.
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Affiliation(s)
- Mansoureh Barzegar
- Molecular and Cellular Physiology, Ochsner-LSU Health Sciences Center, Shreveport, Louisiana, USA
| | - Shantel Vital
- Molecular and Cellular Physiology, Ochsner-LSU Health Sciences Center, Shreveport, Louisiana, USA
| | - Karen Y Stokes
- Molecular and Cellular Physiology, Ochsner-LSU Health Sciences Center, Shreveport, Louisiana, USA
| | - Yuping Wang
- Obstetrics and Gynecology and Medicine, Ochsner-LSU Health Sciences Center, Shreveport, Louisiana, USA
| | - Jungmi Winny Yun
- Molecular and Cellular Physiology, Ochsner-LSU Health Sciences Center, Shreveport, Louisiana, USA
| | - Luke A White
- Molecular and Cellular Physiology, Ochsner-LSU Health Sciences Center, Shreveport, Louisiana, USA
| | - Oleg Chernyshev
- Neurology, Ochsner-LSU Health Sciences Center, Shreveport, Louisiana, USA
| | - Roger E Kelley
- Neurology, Ochsner-LSU Health Sciences Center, Shreveport, Louisiana, USA
| | - Jonathan S Alexander
- Molecular and Cellular Physiology, Ochsner-LSU Health Sciences Center, Shreveport, Louisiana, USA.,Neurology, Ochsner-LSU Health Sciences Center, Shreveport, Louisiana, USA
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15
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de Moura SS, Mendes ATP, de Assis Dias Martins-Júnior F, Totou NL, Coelho DB, Oliveira ECD, Motta-Santos D, Dos Santos RAS, Becker LK. Angiotensin-(1-7) oral formulation improves physical performance in mountain bike athletes: a double-blinded crossover study. BMC Sports Sci Med Rehabil 2021; 13:47. [PMID: 33957973 PMCID: PMC8101253 DOI: 10.1186/s13102-021-00274-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 04/22/2021] [Indexed: 11/23/2022]
Abstract
BACKGROUND The ECA2/Ang-(1-7)/Mas axis is shown to be involved in effects mediated by physical exercise, as it can induce the release of nitric oxide (ON) and bradykinin (BK), which are potent vasodilators. The vasodilating action the NO/BK can contribute to increased metabolic efficiency in muscle tissue and central nervous system. The formulation HPβ-CD-Ang-(1-7) through its mechanisms of action can be a promising supplement to aid in the maintenance and improvement of performance and may also favor recovery during competitions. The premise of this study was to investigate the effects of acute oral supplementation HPβ-CD-Ang-(1-7) on the performance of mountain bike (MTB) practitioners. METHODS Fourteen recreational athletes, involved in training programs for at least one year, participated in this crossover design study. Subjects underwent two days of testing with a seven-day interval. HPβ-CD-Ang-(1-7) (1.75 mg) and HPβCD-Placebo were provided in capsules three hours prior to tests. To determine the safety of the HPβ-CD-Ang-(1-7) formulation associated with physical effort, cardiovascular parameters heart rate (HR) and blood pressure (BP) were analyzed. Physical performance was measured using maximal oxygen uptake (VO2), total exercise time (TET), mechanical work (MW), mechanical efficiency (ME), and rating of perceived exertion (RPE). Respiratory exchange coefficient (REC), lactate and non-esterified fatty acids (NEFAs) were measured. Maximal incremental tests were performed on a progressively loaded leg cycle ergometer. RESULTS There were no significant differences in terms of HR or BP at rest and maximum effort between the HPβ-CD-Ang-(1-7) and placebo groups. The VO2max showed significant differences (p = 0.04). It was higher in the Ang-(1-7)condition (66.15 mlO2.kg- 1.min- 1) compared to the placebo (60.72 mlO2.kg- 1.min- 1). This was also observed for TET (Ang-(1-7) 39.10 min vs. placebo 38.14 min; p = 0.04), MW (Ang-(1-7) 156.7 vs. placebo 148.2; p = 0.04), and at the lowest RPE (Ang-(1-7) vs. placebo; p = 0.009). No significant differences were observed for REC, NEFAs, or Lactate. CONCLUSIONS These results suggest that HPβ-CD-Ang-(1-7) improves the physical performance of MTB recreational athletes and could be a promising supplement. TRIAL REGISTRATION RBR-2 × 56pw8, registered January 15th, 2021. The study was prospectively registered.
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Affiliation(s)
- Samara Silva de Moura
- Postgraduate Program in Health and Nutrition/PPGSN, Federal University of Ouro Preto, Ouro Preto, Brazil
| | | | | | - Nádia Lúcia Totou
- Postgraduate Program in Biological Sciences, Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Daniel Barbosa Coelho
- Postgraduate Program in Health and Nutrition/PPGSN, Federal University of Ouro Preto, Ouro Preto, Brazil
- Physical Education School, Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Emerson Cruz de Oliveira
- Postgraduate Program in Health and Nutrition/PPGSN, Federal University of Ouro Preto, Ouro Preto, Brazil
- Physical Education School, Federal University of Ouro Preto, Ouro Preto, Brazil
| | - Daisy Motta-Santos
- Department of Sports, School of Physical Education, Physiotherapy and Occupational Therapy, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Robson Augusto Souza Dos Santos
- Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil.
| | - Lenice Kappes Becker
- Postgraduate Program in Health and Nutrition/PPGSN, Federal University of Ouro Preto, Ouro Preto, Brazil.
- Physical Education School, Federal University of Ouro Preto, Ouro Preto, Brazil.
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16
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Senger N, C Parletta A, Marques BVD, Akamine EH, Diniz GP, Campagnole-Santos MJ, Santos RAS, Barreto-Chaves MLM. Angiotensin-(1-7) prevents T3-induced cardiomyocyte hypertrophy by upregulating FOXO3/SOD1/catalase and downregulating NF-ĸB. J Cell Physiol 2021; 236:3059-3072. [PMID: 32964425 DOI: 10.1002/jcp.30069] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 09/08/2020] [Accepted: 09/11/2020] [Indexed: 11/05/2022]
Abstract
Clinical studies have shown a correlation between thyroid disorders and cardiac diseases. High levels of triiodothyronine (T3) induce cardiac hypertrophy, a risk factor for cardiac complications and heart failure. Previous results have demonstrated that angiotensin-(1-7) is able to block T3-induced cardiac hypertrophy; however, the molecular mechanisms involved in this event have not been fully elucidated. Here, we evidenced the contribution of FOXO3 signaling to angiotensin-(1-7) effects. Angiotensin-(1-7) treatment increased nuclear FOXO3 levels and reduced p-FOXO3 levels (inactive form) in isolated cardiomyocytes. Knockdown of FOXO3 by RNA silencing abrogated the antihypertrophic effect of angiotensin-(1-7). Increased expression of antioxidant enzymes superoxide dismutase 1 (SOD1 and catalase) and lower levels of reactive oxygen species and nuclear factor-κB (NF-κB) were observed after angiotensin-(1-7) treatment in vitro. Consistent with these results, transgenic rats overexpressing angiotensin-(1-7) displayed increased nuclear FOXO3 and SOD1 levels and reduced NF-κB levels in the heart. These results provide a new molecular mechanism responsible for the antihypertrophic effect of angiotensin-(1-7), which may contribute to future therapeutic targets.
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Affiliation(s)
- Nathalia Senger
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
| | - Aline C Parletta
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
| | - Bruno V D Marques
- Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
| | - Eliana H Akamine
- Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
| | - Gabriela P Diniz
- Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil
| | - Maria J Campagnole-Santos
- Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Robson A S Santos
- Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
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17
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Niu J, Song W, Li R, Yu H, Guan J, Qi J, He Y. The Bdkrb2 gene family provides a novel view of viviparity adaptation in Sebastes schlegelii. BMC Ecol Evol 2021; 21:44. [PMID: 33731008 PMCID: PMC7968187 DOI: 10.1186/s12862-021-01774-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 03/07/2021] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Black rockfish (Sebastes schlegelii) is a viviparous teleost. We proposed that the rockfish ovarian wall had a similar function to the uterus of mammals previously. In the present study, the well-developed vascular system was observed in the ovarian wall and the exterior surface of the egg membrane. In gestation, adaptation of the ovary vasculature to the rising needs of the embryos occurs through both vasodilation and neovascularization. Bdkrb2, encoding a receptor for bradykinin, plays a critical role in the control of vasodilatation by regulating nitric oxide production. RESULTS Eight Bdkrb2 genes were identified in the black rockfish genome. These genes were located on chromosome 14, which are arranged in a tandem array, forming a gene cluster spanning 50 kb. Protein structure prediction, phylogenetic analysis, and transcriptome analysis showed that eight Bdkrb2 genes evolved two kinds of protein structure and three types of tissue expression pattern. Overexpression of two Bdkrb2 genes in zebrafish indicated a role of them in blood vessel formation or remodeling, which is an important procedure for the viviparous rockfish getting prepared for fertilization and embryos implantation. CONCLUSIONS Our study characterizes eight Bdrkb2 genes in the black rockfish, which may contribute to preparation for fertilization and embryo implantation. This research provides a novel view of viviparity adaptation and lays the groundwork for future research into vascular regulation of ovarian tissue in the breeding cycle in black rockfish.
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Affiliation(s)
- Jingjing Niu
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, Qingdao, 266003, China
| | - Weihao Song
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, Qingdao, 266003, China
| | - Rui Li
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, Qingdao, 266003, China
| | - Haiyang Yu
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, Qingdao, 266003, China
| | - Jian Guan
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, Qingdao, 266003, China
| | - Jie Qi
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, Qingdao, 266003, China
| | - Yan He
- MOE Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, Qingdao, 266003, China.
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18
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Cohen JB, South AM, Shaltout HA, Sinclair MR, Sparks MA. Renin-angiotensin system blockade in the COVID-19 pandemic. Clin Kidney J 2021; 14:i48-i59. [PMID: 33796285 PMCID: PMC7929063 DOI: 10.1093/ckj/sfab026] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 01/19/2021] [Indexed: 01/08/2023] Open
Abstract
In the early months of the coronavirus disease 2019 (COVID-19) pandemic, a hypothesis emerged suggesting that pharmacologic inhibitors of the renin–angiotensin system (RAS) may increase COVID-19 severity. This hypothesis was based on the role of angiotensin-converting enzyme 2 (ACE2), a counterregulatory component of the RAS, as the binding site for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), allowing viral entry into host cells. Extrapolations from prior evidence led to speculation that upregulation of ACE2 by RAS blockade may increase the risk of adverse outcomes from COVID-19. However, counterarguments pointed to evidence of potential protective effects of ACE2 and RAS blockade with regard to acute lung injury, as well as substantial risks from discontinuing these commonly used and important medications. Here we provide an overview of classic RAS physiology and the crucial role of ACE2 in systemic pathways affected by COVID-19. Additionally, we critically review the physiologic and epidemiologic evidence surrounding the interactions between RAS blockade and COVID-19. We review recently published trial evidence and propose important future directions to improve upon our understanding of these relationships.
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Affiliation(s)
- Jordana B Cohen
- Renal-Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Andrew M South
- Section of Nephrology, Department of Pediatrics, Brenner Children's Hospital, Wake Forest School of Medicine, Winston Salem, NC, USA.,Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston Salem, NC, USA.,Department of Surgery, Hypertension and Vascular Research, Wake Forest School of Medicine, Winston Salem, NC, USA.,Cardiovascular Sciences Center, Wake Forest School of Medicine, Winston Salem, NC, USA
| | - Hossam A Shaltout
- Department of Surgery, Hypertension and Vascular Research, Wake Forest School of Medicine, Winston Salem, NC, USA.,Cardiovascular Sciences Center, Wake Forest School of Medicine, Winston Salem, NC, USA.,Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston Salem, NC, USA.,Department of Pharmacology and Toxicology, School of Pharmacy, University of Alexandria, Alexandria, Egypt
| | - Matthew R Sinclair
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA.,Duke Clinical Research Institute, Durham, NC, USA
| | - Matthew A Sparks
- Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA.,Renal Section, Durham VA Health Care System, Durham, NC, USA
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19
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Erfinanda L, Ravindran K, Kohse F, Gallo K, Preissner R, Walther T, Kuebler WM. Oestrogen-mediated upregulation of the Mas receptor contributes to sex differences in acute lung injury and lung vascular barrier regulation. Eur Respir J 2021; 57:13993003.00921-2020. [PMID: 32764118 DOI: 10.1183/13993003.00921-2020] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 07/30/2020] [Indexed: 11/05/2022]
Abstract
Epidemiological data from the SARS-CoV-2 outbreak suggest sex differences in mortality and vulnerability; however, sex-dependent incidence of acute respiratory distress syndrome (ARDS) remains controversial and the sex-dependent mechanisms of endothelial barrier regulation are unknown. In premenopausal women, increased signalling of angiotensin (Ang)(1-7) via the Mas receptor has been linked to lower cardiovascular risk. Since stimulation of the Ang(1-7)/Mas axis protects the endothelial barrier in acute lung injury (ALI), we hypothesised that increased Ang(1-7)/Mas signalling may protect females over males in ALI/ARDS.Clinical data were collected from Charité inpatients (Berlin) and sex differences in ALI were assessed in wild-type (WT) and Mas-receptor deficient (Mas-/- ) mice. Endothelial permeability was assessed as weight change in isolated lungs and as transendothelial electrical resistance (TEER) in vitroIn 734 090 Charité inpatients (2005-2016), ARDS had a higher incidence in men as compared to women. In murine ALI, male WT mice had more lung oedema, protein leaks and histological evidence of injury than female WT mice. Lung weight change in response to platelet-activating factor (PAF) was more pronounced in male WT and female Mas-/- mice than in female WT mice, whereas Mas-receptor expression was higher in female WT lungs. Ovariectomy attenuated protection in female WT mice and reduced Mas-receptor expression. Oestrogen increased Mas-receptor expression and attenuated endothelial leakage in response to thrombin in vitro This effect was alleviated by Mas-receptor blockade.Improved lung endothelial barrier function protects female mice from ALI-induced lung oedema. This effect is partially mediated via enhanced Ang(1-7)/Mas signalling as a result of oestrogen-dependent Mas expression.
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Affiliation(s)
- Lasti Erfinanda
- Institute of Physiology, Charité - Universitätsmedizin, Berlin, Germany
| | - Krishnan Ravindran
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON, Canada
| | - Franziska Kohse
- Institute of Physiology, Charité - Universitätsmedizin, Berlin, Germany.,Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald, Germany
| | - Kathleen Gallo
- Institute of Physiology, Charité - Universitätsmedizin, Berlin, Germany
| | - Robert Preissner
- Institute of Physiology, Charité - Universitätsmedizin, Berlin, Germany
| | - Thomas Walther
- Institute of Medical Biochemistry and Molecular Biology, University Medicine Greifswald, Greifswald, Germany .,Dept of Pharmacology and Therapeutics, School of Medicine, University College Cork, Cork, Ireland.,Shared senior authorship
| | - Wolfgang M Kuebler
- Institute of Physiology, Charité - Universitätsmedizin, Berlin, Germany.,Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, ON, Canada.,Dept of Physiology and Dept of Surgery, University of Toronto, Toronto, ON, Canada.,Shared senior authorship
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20
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Tsai HJ, Shih CC, Chang KY, Liao MH, Liaw WJ, Wu CC, Tsao CM. Angiotensin-(1-7) treatment blocks lipopolysaccharide-induced organ damage, platelet dysfunction, and IL-6 and nitric oxide production in rats. Sci Rep 2021; 11:610. [PMID: 33436885 PMCID: PMC7804205 DOI: 10.1038/s41598-020-79902-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 12/14/2020] [Indexed: 12/29/2022] Open
Abstract
Sepsis can lead to shock, multiple organ failure, and even death. Platelets play an active role in the pathogenesis of sepsis-induced multiple organ failure. Angiotensin (Ang)-(1–7), a biologically active peptide, counteracts various effects of Ang II and attenuates inflammatory responses, reactive oxygen species production, and apoptosis. We evaluated the effects of Ang-(1–7) on organ injury and platelet dysfunction in rats with endotoxaemia. We treated male Wistar rats with saline or lipopolysaccharide (LPS, 10 mg, intravenously) then Ang-(1–7) (1 mg/kg, intravenous infusion for 3 h beginning 30 min after LPS administration). We analysed several haemodynamic, biochemical, and inflammatory parameters, as well as platelet counts and aggregation. Ang-(1–7) improved hypotension and organ dysfunction, and attenuated plasma interleukin-6, chemokines and nitric oxide production in rats after LPS administration. The LPS-induced reduction in platelet aggregation, but not the decreased platelet count, was restored after Ang-(1–7) treatment. The protein expression of iNOS and IκB, but not phosphorylated ERK1/2 and p38, was diminished in Ang-(1–7)-treated LPS rats. The histological changes in liver and lung were significantly attenuated in Ang-(1–7)-treated LPS rats. Our results suggest that Ang-(1–7) ameliorates endotoxaemic-induced organ injury and platelet dysfunction, likely through the inhibition of the inflammatory response and nitric oxide production.
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Affiliation(s)
- Hsin-Jung Tsai
- Department of Anesthesiology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei, 112, Taiwan
| | - Chih-Chin Shih
- Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan
| | - Kuang-Yi Chang
- Department of Anesthesiology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei, 112, Taiwan.,Department of Anesthesiology, National Yang-Ming University, Taipei, Taiwan
| | - Mei-Hui Liao
- Department of Nursing, Oriental Institute of Technology, New Taipei City, Taiwan
| | - Wen-Jinn Liaw
- Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan.,Department of Anesthesiology, Chung Shan Medical University and Hospital, Taichung, Taiwan
| | - Chin-Chen Wu
- Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan
| | - Cheng-Ming Tsao
- Department of Anesthesiology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou District, Taipei, 112, Taiwan. .,Department of Anesthesiology, National Yang-Ming University, Taipei, Taiwan. .,Department of Anesthesiology, National Defense Medical Center, Taipei, Taiwan.
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21
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de Sousa GG, Barbosa MA, Barbosa CM, Lima TC, Souza Dos Santos RA, Campagnole-Santos MJ, Alzamora AC. Different reactive species modulate the hypotensive effect triggered by angiotensins at CVLM of 2K1C hypertensive rats. Peptides 2020; 134:170409. [PMID: 32950566 DOI: 10.1016/j.peptides.2020.170409] [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: 04/15/2020] [Revised: 08/20/2020] [Accepted: 09/15/2020] [Indexed: 11/18/2022]
Abstract
Hypertension is associated with increased central activity of the renin-angiotensin system (RAS) and oxidative stress. Here, we evaluated whether reactive species and neurotransmitters could contribute to the hypotensive effect induced by angiotensin (Ang) II and Ang-(1-7) at the caudal ventrolateral medulla (CVLM) in renovascular hypertensive rats (2K1C). Therefore, we investigated the effect of Ang II, Ang-(1-7), and the Ang-(1-7) antagonist A-779 microinjected before and after CVLM microinjection of the nitric oxide (NO)-synthase inhibitor, (L-NAME), vitamin C (Vit C), bicuculline, or kynurenic acid in 2K1C and SHAM rats. Baseline values of the mean arterial pressure (MAP) in 2K1C rats were higher than in SHAM rats. CVLM microinjection of Ang II, Ang-(1-7), l-NAME, or bicuculline induced decreases in the MAP in SHAM and 2K1C rats. In addition, Vit C and A-779 produced decreases in the MAP only in 2K1C rats. Kynurenic acid increased the MAP in both SHAM and 2K1C rats. Only the Ang-(1-7) effect was increased by l-NAME and reduced by bicuculline in SHAM rats. L-NAME also reduced the A-779 effect in 2K1C rats. Only the Ang II effect was abolished by CVLM Vit C and enhanced by CVLM kynurenic acid in SHAM and 2K1C rats. Overall, the superoxide anion and glutamate participated in the hypotensive effect of Ang II, while NO and GABA participated in the hypotensive effect of Ang-(1-7) in CVLM. The higher hypotensive response of A-779 in the CVLM of 2K1C rats suggests that Ang-(1-7) contributes to renovascular hypertension.
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Affiliation(s)
- Graziele Galdino de Sousa
- Núcleo de Pesquisa em Ciências Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, MG, Brazil
| | - Maria Andréa Barbosa
- Núcleo de Pesquisa em Ciências Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, MG, Brazil
| | - Claudiane Maria Barbosa
- Núcleo de Pesquisa em Ciências Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, MG, Brazil
| | - Taynara Carolina Lima
- Núcleo de Pesquisa em Ciências Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, MG, Brazil
| | - Robson Augusto Souza Dos Santos
- Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Maria José Campagnole-Santos
- Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Andréia Carvalho Alzamora
- Departamento de Ciências Biológicas, Instituto de Ciências Exatas e Biológicas, Brazil; Núcleo de Pesquisa em Ciências Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, MG, Brazil.
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22
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Del Turco S, Vianello A, Ragusa R, Caselli C, Basta G. COVID-19 and cardiovascular consequences: Is the endothelial dysfunction the hardest challenge? Thromb Res 2020; 196:143-151. [PMID: 32871306 PMCID: PMC7451195 DOI: 10.1016/j.thromres.2020.08.039] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 08/17/2020] [Accepted: 08/26/2020] [Indexed: 12/22/2022]
Abstract
A Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) has become a pandemic disease named Coronavirus Disease-19 (COVID-19) of epochal dimension. The clinical spectrum of COVID-19 is wide, ranging from asymptomatic forms to severe pneumonia, sepsis and multiple organ dysfunction syndromes resulting in poor outcomes. Among the various consequences of severe COVID-19, cardiovascular (CV) collapse appears the most serious and potentially lethal. On the other hand, pre-existent CV comorbidities are also associated with higher mortality. The most reliable hypothetical pathogenetic mechanism for CV complications and cardiac injury in severe COVID-19 patients appears to be a sustained endothelial dysfunction, caused by the interplay of inflammation and coagulation. In this review, we survey papers addressing issues related to severe COVID-19, characterized by enhanced lung microvascular loss, hypercytokinemia, hypoxemia and thrombosis. We discuss about how the virus-induced downregulation of the angiotensin converting enzyme-2 (ACE2) receptor, used to enter the host cell, could affect the renin-angiotensin system, attempting to clarify the doubts about the use of ACE inhibitors and Angiotensin-II receptor blockers in COVID-19 patients. Finally, we point out how the delicate and physiological homeostatic function of the endothelium, which turns into a disastrous battlefield of the complex interaction between "cytokine and coagulative storms", can be irreparably compromised and result in systemic inflammatory complications.
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Affiliation(s)
- Serena Del Turco
- Institute of Clinical Physiology, CNR, San Cataldo Research Area, Via Moruzzi, 1, 56124 Pisa, Italy.
| | - Annamaria Vianello
- Department of Information Engineering, Telemedicine Section, University of Pisa, Italy
| | - Rosetta Ragusa
- Institute of Clinical Physiology, CNR, San Cataldo Research Area, Via Moruzzi, 1, 56124 Pisa, Italy
| | - Chiara Caselli
- Institute of Clinical Physiology, CNR, San Cataldo Research Area, Via Moruzzi, 1, 56124 Pisa, Italy
| | - Giuseppina Basta
- Institute of Clinical Physiology, CNR, San Cataldo Research Area, Via Moruzzi, 1, 56124 Pisa, Italy.
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23
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Xin L, Gao J, Lin H, Qu Y, Shang C, Wang Y, Lu Y, Cui X. Regulatory Mechanisms of Baicalin in Cardiovascular Diseases: A Review. Front Pharmacol 2020; 11:583200. [PMID: 33224035 PMCID: PMC7667240 DOI: 10.3389/fphar.2020.583200] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 09/15/2020] [Indexed: 12/17/2022] Open
Abstract
Cardiovascular diseases (CVDs) is the leading cause of high morbidity and mortality worldwide, which emphasizes the urgent necessity to develop new pharmacotherapies. In eastern countries, traditional Chinese medicine Scutellaria baicalensis Georgi has been used clinically for thousands of years. Baicalin is one of the main active ingredients extracted from Chinese herbal medicine S. baicalensis. Emerging evidence has established that baicalin improves chronic inflammation, immune imbalance, disturbances in lipid metabolism, apoptosis and oxidative stress. Thereby it offers beneficial roles against the initiation and progression of CVDs such as atherosclerosis, hypertension, myocardial infarction and reperfusion, and heart failure. In this review, we summarize the pharmacological features and relevant mechanisms by which baicalin regulates CVDs in the hope to reveal its application for CVDs prevention and/or therapy.
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Affiliation(s)
- Laiyun Xin
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China.,Department of Cardiology, Guang' anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jialiang Gao
- Department of Cardiology, Guang' anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Hongchen Lin
- Department of Cardiology, Guang' anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yi Qu
- Department of Cardiology, Guang' anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Chang Shang
- Department of Cardiology, Guang' anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yuling Wang
- Department of Cardiology, Guang' anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yingdong Lu
- Department of Cardiology, Guang' anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiangning Cui
- Department of Cardiology, Guang' anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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Gunarathne LS, Rajapaksha H, Shackel N, Angus PW, Herath CB. Cirrhotic portal hypertension: From pathophysiology to novel therapeutics. World J Gastroenterol 2020; 26:6111-6140. [PMID: 33177789 PMCID: PMC7596642 DOI: 10.3748/wjg.v26.i40.6111] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/28/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Portal hypertension and bleeding from gastroesophageal varices is the major cause of morbidity and mortality in patients with cirrhosis. Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is characterized by a high cardiac output, increased total blood volume and splanchnic vasodilatation, resulting in increased mesenteric blood flow. Pharmacological manipulation of cirrhotic portal hypertension targets both the splanchnic and hepatic vascular beds. Drugs such as angiotensin converting enzyme inhibitors and angiotensin II type receptor 1 blockers, which target the components of the classical renin angiotensin system (RAS), are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and vasoactivity of contractile cells and thereby improve portal hypertension. However, these drugs have been shown to produce significant off-target effects such as systemic hypotension and renal failure. Therefore, the current pharmacological mainstay in clinical practice to prevent variceal bleeding and improving patient survival by reducing portal pressure is non-selective -blockers (NSBBs). These NSBBs work by reducing cardiac output and splanchnic vasodilatation but most patients do not achieve an optimal therapeutic response and a significant proportion of patients are unable to tolerate these drugs. Although statins, used alone or in combination with NSBBs, have been shown to improve portal pressure and overall mortality in cirrhotic patients, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points. On the other hand, recent findings from studies that have investigated the potential use of the blockers of the components of the alternate RAS provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilatation in portal hypertension. This review outlines the mechanisms related to the pathogenesis of portal hypertension and attempts to provide an update on currently available therapeutic approaches in the management of portal hypertension with special emphasis on how the alternate RAS could be manipulated in our search for development of safe, specific and effective novel therapies to treat portal hypertension in cirrhosis.
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Affiliation(s)
- Lakmie S Gunarathne
- Department of Medicine, Melbourne Medical School, The University of Melbourne, Heidelberg, VIC 3084, Australia
| | - Harinda Rajapaksha
- School of Molecular Science, College of Science, Health and Engineering, La Trobe University, Bundoora, VIC 3086, Australia
| | | | - Peter W Angus
- Department of Gastroenterology, Austin Health, Heidelberg, VIC 3084, Australia
| | - Chandana B Herath
- Department of Medicine, Melbourne Medical School, The University of Melbourne, Heidelberg, VIC 3084, Australia
- South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Ingham Institute for Applied Medical Research, 1 Campbell Street, Liverpool, NSW 2170, Australia
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25
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Sartório CL, Pimentel EB, Dos Santos RL, Rouver WN, Mill JG. Acute hypotensive effect of diminazene aceturate in spontaneously hypertensive rats: role of NO and Mas receptor. Clin Exp Pharmacol Physiol 2020; 47:1723-1730. [PMID: 32603499 DOI: 10.1111/1440-1681.13368] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 06/19/2020] [Accepted: 06/24/2020] [Indexed: 01/22/2023]
Abstract
Diminazene aceturate (DIZE) has been described as an angiotensin-converting enzyme 2 (ACE2) activator. We aimed to investigate DIZE effects on blood pressure (BP) of spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats. BP was recorded in awake and unrestrained rats 24 hours after femoral artery catheterization. DIZE (15 mg/kg, s.c.) produced a fast BP decrease only in SHR (P < .01). Pre-treatment with L-NAME (10 mg/kg, iv) did not change the hypotensive effect on systolic BP whereas mitigated the DIZE effect on diastolic BP (∆ Emax: -31 ± 5 DIZE vs -15 ± 1 mm Hg DIZE + L-NAME, P < .05). BP changes after DIZE remained unchanged after the treatment of rats with A-779 (50 ug/kg, iv), a Mas receptor blocker. Vasodilatation curves to DIZE (10-9 to 10-4 mol/L) in mesenteric arteries confirmed the NO-mediation on DIZE effects in SHR, as L-NAME (300 μmol/L) reduced the vascular sensitivity (∆EC50: -5.12 ± 0.09 CONTROL vs -4.66 ± 0.08 L-NAME, P < .05) and the magnitude of DIZE effect (area under the curve (AUC), 357.5 ± 8.2 DIZE vs 424.7 ± 11.6 L-NAME; P < .001), whereas A-779 (1 μmol/L) enhanced DIZE response (AUC, 357.5 ± 8.2 DIZE vs 309.8 ± 14.7 A-779, P < .05). Our findings indicate that DIZE acutely reduces the BP in SHR possibly by a mechanism other than Mas receptor activation. This effect seems to be mediated, at least partially, by NO.
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Affiliation(s)
- Carmem Luíza Sartório
- Department of Physiological Sciences, Federal University of Espirito Santo (UFES), Espirito Santo, Brazil
| | - Enildo Broetto Pimentel
- Department of Physiological Sciences, Federal University of Espirito Santo (UFES), Espirito Santo, Brazil
| | - Roger Lyrio Dos Santos
- Department of Physiological Sciences, Federal University of Espirito Santo (UFES), Espirito Santo, Brazil
| | - Wender N Rouver
- Department of Physiological Sciences, Federal University of Espirito Santo (UFES), Espirito Santo, Brazil
| | - Jose Geraldo Mill
- Department of Physiological Sciences, Federal University of Espirito Santo (UFES), Espirito Santo, Brazil
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Fetal Growth Restriction and Hypertension in the Offspring: Mechanistic Links and Therapeutic Directions. J Pediatr 2020; 224:115-123.e2. [PMID: 32450071 PMCID: PMC8086836 DOI: 10.1016/j.jpeds.2020.05.028] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 05/14/2020] [Accepted: 05/14/2020] [Indexed: 12/24/2022]
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Glassman PM, Myerson JW, Ferguson LT, Kiseleva RY, Shuvaev VV, Brenner JS, Muzykantov VR. Targeting drug delivery in the vascular system: Focus on endothelium. Adv Drug Deliv Rev 2020; 157:96-117. [PMID: 32579890 PMCID: PMC7306214 DOI: 10.1016/j.addr.2020.06.013] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 06/12/2020] [Accepted: 06/13/2020] [Indexed: 12/16/2022]
Abstract
The bloodstream is the main transporting pathway for drug delivery systems (DDS) from the site of administration to the intended site of action. In many cases, components of the vascular system represent therapeutic targets. Endothelial cells, which line the luminal surface of the vasculature, play a tripartite role of the key target, barrier, or victim of nanomedicines in the bloodstream. Circulating DDS may accumulate in the vascular areas of interest and in off-target areas via mechanisms bypassing specific molecular recognition, but using ligands of specific vascular determinant molecules enables a degree of precision, efficacy, and specificity of delivery unattainable by non-affinity DDS. Three decades of research efforts have focused on specific vascular targeting, which have yielded a multitude of DDS, many of which are currently undergoing a translational phase of development for biomedical applications, including interventions in the cardiovascular, pulmonary, and central nervous systems, regulation of endothelial functions, host defense, and permeation of vascular barriers. We discuss the design of endothelial-targeted nanocarriers, factors underlying their interactions with cells and tissues, and describe examples of their investigational use in models of acute vascular inflammation with an eye on translational challenges.
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Affiliation(s)
- Patrick M Glassman
- Department of Systems Pharmacology and Translational Therapeutics, Center for Targeted Therapeutics and Translational Nanomedicine of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America.
| | - Jacob W Myerson
- Department of Systems Pharmacology and Translational Therapeutics, Center for Targeted Therapeutics and Translational Nanomedicine of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America
| | - Laura T Ferguson
- Department of Systems Pharmacology and Translational Therapeutics, Center for Targeted Therapeutics and Translational Nanomedicine of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America; Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America
| | - Raisa Y Kiseleva
- Department of Systems Pharmacology and Translational Therapeutics, Center for Targeted Therapeutics and Translational Nanomedicine of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America
| | - Vladimir V Shuvaev
- Department of Systems Pharmacology and Translational Therapeutics, Center for Targeted Therapeutics and Translational Nanomedicine of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America
| | - Jacob S Brenner
- Department of Systems Pharmacology and Translational Therapeutics, Center for Targeted Therapeutics and Translational Nanomedicine of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America; Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America
| | - Vladimir R Muzykantov
- Department of Systems Pharmacology and Translational Therapeutics, Center for Targeted Therapeutics and Translational Nanomedicine of the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States of America.
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Autocrine Bradykinin Release Promotes Ischemic Preconditioning-Induced Cytoprotection in Bovine Aortic Endothelial Cells. Int J Mol Sci 2020; 21:ijms21082965. [PMID: 32340102 PMCID: PMC7215376 DOI: 10.3390/ijms21082965] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 04/18/2020] [Accepted: 04/18/2020] [Indexed: 12/27/2022] Open
Abstract
The aims of this study were to assess whether ischemic preconditioning (PC) induces bradykinin (Bk) synthesis in bovine aortic endothelial cells (bAECs) and, if so, to explore the molecular mechanisms by which this peptide provides cytoprotection against hypoxia. PC was induced by exposing bAECs to three cycles of 15 min of hypoxia followed by 15 min of reoxygenation. Bk synthesis peaked in correspondence to the early and late phases of PC (10−12 M and 10−11 M, respectively) and was abolished by a selective tissue kallikrein inhibitor, aprotinin. Stimulation with exogenous Bk at concentrations of 10−12 M and 10−11 M reduced the cell death induced by 12 h of hypoxia by 50%. Pretreatment with HOE−140, a Bk receptor 2 (BKR2) inhibitor, in bAECs exposed to 12 h of hypoxia, abrogated the cytoprotective effect of early and late PC, whereas des-Arg-HOE-140, a Bk receptor 1 (BKR1) inhibitor, affected only the late PC. In addition, we found that PC evoked endocytosis and the recycling of BKR2 during both the early and late phases, and that inhibition of these pathways affected PC-mediated cytoprotection. Finally, we evaluated the activation of PKA and Akt in the presence or absence of BKR2 inhibitor. HOE-140 abrogated PKA and Akt activation during both early and late PC. Consistently, BKR2 inhibition abolished cross-talk between PKA and Akt in PC. In bAECs, Bk-synthesis evoked by PC mediates the protection against both apoptotic and necrotic hypoxia-induced cell death in an autocrine manner, by both BKR2- and BKR1-dependent mechanisms.
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29
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Malinski T, Dawoud H. Vitamin D3, L-Arginine, L-Citrulline, and antioxidant supplementation enhances nitric oxide bioavailability and reduces oxidative stress in the vascular endothelium – Clinical implications for cardiovascular system. Pharmacognosy Res 2020. [DOI: 10.4103/pr.pr_79_19] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Sankhe R, Kinra M, Mudgal J, Arora D, Nampoothiri M. Neprilysin, the kidney brush border neutral proteinase: a possible potential target for ischemic renal injury. Toxicol Mech Methods 2019; 30:88-99. [PMID: 31532266 DOI: 10.1080/15376516.2019.1669246] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Neprilysin (NEP) is an endogenously induced peptidase for modulating production and degradation of various peptides in humans. It is most abundantly present in kidney and regulates the intrinsic renal homeostatic mechanism. Recently, drugs inhibiting NEP have been approved for the use in heart failure. In the context of increased prevalence of ischemia associated renal failure, NEP could be an attractive target for treating kidney failure. In the kidney, targeting NEP may possess potential benefits as well as adverse consequences. The unfavorable outcomes of NEP are mainly attributed to the degradation of the natriuretic peptides (NPs). NPs are involved in the inhibition of the renin-angiotensin-aldosterone system (RAAS) and activation of the sympathetic system contributing to the tubular and glomerular injury. In contrary, NEP exerts the beneficial effect by converting angiotensin-1 (Ang I) to angiotensin-(1-7) (Ang-(1-7)), thus activating MAS-related G-protein coupled receptor. MAS receptor antagonizes angiotensin type I receptor (AT-1R), reduces reactive oxygen species (ROS) and inflammation, thus ameliorating renal injury. However, the association of NEP with complex cascades of renal ischemia remains vague. Therefore, there is a need to evaluate the putative mechanism of NEP and its overlap with other signaling cascades in conditions of renal ischemia.
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Affiliation(s)
- Runali Sankhe
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Manas Kinra
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Jayesh Mudgal
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India
| | - Devinder Arora
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India.,School of Pharmacy and Pharmacology, MHIQ, QUM Network, Griffith University, Gold Coast, Australia
| | - Madhavan Nampoothiri
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India
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31
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Safari T, Shahraki MR, Miri S, Mirakzehi Bakhshani N, Niazi AA, Komeili GR, Bagheri H. The effect of angiotensin 1-7 and losartan on renal ischemic/reperfusion injury in male rats. Res Pharm Sci 2019; 14:441-447. [PMID: 31798661 PMCID: PMC6827188 DOI: 10.4103/1735-5362.268205] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Ischemia/reperfusion (I/R) is a major cause of acute kidney injury. Several studies have shown that renin angiotensin (Ang) system and activation of Ang II type 1 receptor (AT1) are involved in various forms of kidney diseases. Likewise, Ang 1-7 as a physiologic antagonist of AT1 and losartan could possibly protect the kidney against I/R damage. Therefore, we investigated renal injury by administering the drugs before and after I/R. Fifty-four male Wistar rats were randomly assigned to five groups as follows. 1, Sham operated; 2, saline group (as a control group); 3, losartan group; 4, Ang 1-7group; and 5, Ang 1-7 + losartan simultaneously. It should be noted that groups 2-5 consisted of two separate I/R-induced subgroups both receiving medication where the first groups received the treatment 15 min before induction of I/R while the medications were given to the second groups immediately after induction of I/R. Twenty four h after I/R, blood samples were collected, and then levels of serum urea nitrogen (BUN), creatinine (Cr), nitrite, malondialdehyde (MDA), lactate dehydrogenase (LDH) and total antioxidant capacity (TAC) were measured. Likewise, nitrite, MDA and TAC were measured in the homogenized kidney tissues. After the induction of I/R, the BUN, Cr, LDH, and kidney tissue damage score increased. Administration of Ang 1-7 alone or simultaneously with losartan decreased the levels of aforementioned factors. Also, kidney MDA and nitrate levels significantly increased after I/R induction (P < 0.05). According to the results of this study, it can be claimed that the effect of losartan in the presence of Mas receptor is statistically significant and kidney damage dramatically decreases.
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Affiliation(s)
- Tahereh Safari
- School of Medicine, Department of Physiology, Zahedan University of Medical Sciences, Zahedan, I.R. Iran
| | - Mohamad Reza Shahraki
- School of Medicine, Department of Physiology, Zahedan University of Medical Sciences, Zahedan, I.R. Iran
| | - Saideh Miri
- School of Medicine, Department of Physiology, Zahedan University of Medical Sciences, Zahedan, I.R. Iran
| | - Nasime Mirakzehi Bakhshani
- School of Medicine, Department of Physiology, Zahedan University of Medical Sciences, Zahedan, I.R. Iran
| | - Abbass Ali Niazi
- School of Medicine, Department of Pathology, Zahedan University of Medical Sciences, Zahedan, I.R. Iran
| | - Gholam Reza Komeili
- School of Medicine, Department of Physiology, Zahedan University of Medical Sciences, Zahedan, I.R. Iran
| | - Hossain Bagheri
- School of Medicine, Department of Medical English, Zahedan University of Medical Sciences, I.R. Iran
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32
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Gunarathne LS, Angus PW, Herath CB. Blockade of Mas Receptor or Mas-Related G-Protein Coupled Receptor Type D Reduces Portal Pressure in Cirrhotic but Not in Non-cirrhotic Portal Hypertensive Rats. Front Physiol 2019; 10:1169. [PMID: 31607942 PMCID: PMC6761391 DOI: 10.3389/fphys.2019.01169] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 08/29/2019] [Indexed: 12/12/2022] Open
Abstract
Portal hypertension (PHT) resulting from splanchnic vasodilatation is a major cause of morbidity and mortality in patients with cirrhosis. The renin-angiotensin system (RAS) plays an important role in splanchnic vasodilatation in cirrhosis. This study investigated whether acute blockade of the vasodilatory receptors of the alternate RAS, Mas (MasR), Mas-related G-protein coupled receptor type D (MrgD), and angiotensin II type-2 receptor (AT2R) improves PHT in cirrhotic and non-cirrhotic portal hypertensive rats and counteracts systemic hypotension associated with angiotensin II type 1 receptor (AT1R) blockade. Cirrhotic bile duct ligated (BDL) or carbon tetrachloride (CCl4) injected and non-cirrhotic partial portal vein ligated (PPVL) rats were used for measurement of portal pressure (PP) and mean arterial pressure before and after an intravenous bolus injection of the MasR, MrgD, and AT2R blockers, A779, D-Pro7-Ang-(1-7) (D-Pro) and PD123319, respectively. Separate groups of rats received a combined treatment with A779 or D-Pro given 20 min after AT1R blocker losartan. Mesenteric expression of MasR, MrgD, and AT2R and circulating levels of peptide blockers were also measured. Treatment with A779 and D-Pro significantly reduced PP in cirrhotic rat models. Despite rapid degradation of A779 and D-Pro in the rat circulation, the PP lowering effect of the blockers lasted for up to 25 min. We also found that PD123319 reduced PP in CCl4 rats, possibly by blocking the MasR and/or MrgD since AT2R expression in cirrhotic mesenteric vessels was undetectable, whereas the expression of MasR and MrgD was markedly elevated. While losartan resulted in a marked reduction in PP, its profound systemic hypotensive effect was not counteracted by the combination therapy with A779 or D-Pro. In marked contrast, none of the receptor blockers had any effect on PP in non-cirrhotic PPVL rats whose mesenteric expression of MasR and MrgD was unchanged. We conclude that in addition to MasR, MrgD, a newly discovered receptor for Angiotensin-(1-7), plays a key role in splanchnic vasodilatation in cirrhosis. This implies that both MasR and MrgD are potential therapeutic targets to treat PHT in cirrhotic patients. We also conclude that the alternate RAS may not contribute to the development of splanchnic vasodilatation in non-cirrhotic PHT.
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Affiliation(s)
- Lakmie S Gunarathne
- Department of Medicine, The University of Melbourne, Austin Health, Melbourne, VIC, Australia
| | - Peter W Angus
- Department of Medicine, The University of Melbourne, Austin Health, Melbourne, VIC, Australia.,Department of Gastroenterology and Hepatology, Austin Health, Melbourne, VIC, Australia
| | - Chandana B Herath
- Department of Medicine, The University of Melbourne, Austin Health, Melbourne, VIC, Australia
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Abstract
Perivascular adipose tissue (PVAT) refers to the local aggregate of adipose tissue surrounding the vascular tree, exhibiting phenotypes from white to brown and beige adipocytes. Although PVAT has long been regarded as simply a structural unit providing mechanical support to vasculature, it is now gaining reputation as an integral endocrine/paracrine component, in addition to the well-established modulator endothelium, in regulating vascular tone. Since the discovery of anti-contractile effect of PVAT in 1991, the use of multiple rodent models of reduced amounts of PVAT has revealed its regulatory role in vascular remodeling and cardiovascular implications, including atherosclerosis. PVAT does not only release PVAT-derived relaxing factors (PVRFs) to activate multiple subsets of endothelial and vascular smooth muscle potassium channels and anti-inflammatory signals in the vasculature, but it does also provide an interface for neuron-adipocyte interactions in the vascular wall to regulate arterial vascular tone. In this review, we outline our current understanding towards PVAT and attempt to provide hints about future studies that can sharpen the therapeutic potential of PVAT against cardiovascular diseases and their complications.
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Affiliation(s)
- Chak Kwong Cheng
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, SAR, China
- Institute of Vascular Medicine, Shenzhen Research Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Hamidah Abu Bakar
- Health Sciences Department, Universiti Selangor, 40000, Shah Alam, Selangor, Malaysia
| | - Maik Gollasch
- Experimental and Clinical Research Center (ECRC)-a joint cooperation between the Charité-University Medicine Berlin and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125, Berlin, Germany.
- Medical Clinic for Nephrology and Internal Intensive Care, Charité Campus Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany.
| | - Yu Huang
- School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, SAR, China.
- Institute of Vascular Medicine, Shenzhen Research Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, SAR, China.
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Dibo P, Marañón RO, Chandrashekar K, Mazzuferi F, Silva GB, Juncos LA, Juncos LI. Angiotensin-(1-7) inhibits sodium transport via Mas receptor by increasing nitric oxide production in thick ascending limb. Physiol Rep 2019; 7:e14015. [PMID: 30839176 PMCID: PMC6401662 DOI: 10.14814/phy2.14015] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 02/03/2019] [Indexed: 02/07/2023] Open
Abstract
Sodium transport in the thick ascending loop of Henle (TAL) is tightly regulated by numerous factors, especially angiotensin II (Ang II), a key end-product of the renin-angiotensin system (RAS). However, an alternative end-product of the RAS, angiotensin-(1-7) [Ang-(1-7)], may counter some of the Ang II actions. Indeed, it causes vasodilation and promotes natriuresis through its effects in the proximal and distal tubule. However, its effects on the TAL are unknown. Because the TAL expresses the Mas receptor, an Ang-(1-7) ligand, which in turn may increase NO and inhibit Na+ transport, we hypothesized that Ang-(1-7) inhibits Na transport in the TAL, via a Mas receptor/NO-dependent mechanism. We tested this by measuring transport-dependent oxygen consumption (VO2 ) in TAL suspensions. Administering Ang-(1-7) decreased VO2 ; an effect prevented by dimethyl amiloride and furosemide, signifying that Ang-(1-7) inhibits transport-dependent VO2 in TAL. Ang-(1-7) also increased NO levels, known inhibitors of Na+ transport in the TAL. The effects of Ang-(1-7) on VO2 , as well as on NO levels, were ameliorated by the Mas receptor antagonist, D-Ala, in effect suggesting that Ang-(1-7) may inhibit transport-dependent VO2 in TAL via Mas receptor-dependent activation of the NO pathway. Indeed, blocking NO synthesis with L-NAME prevented the inhibitory actions of Ang-(1-7) on VO2 . Our data suggest that Ang-(1-7) may modulate TAL Na+ transport via Mas receptor-dependent increases in NO leading to the inhibition of transport activity.
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Affiliation(s)
- Paula Dibo
- Department of Basic ResearchJ. Robert Cade FoundationCordobaArgentina
| | - Rodrigo O. Marañón
- Department of Medicine/NephrologyUniversity of Mississippi Medical CenterJacksonMississippi
- Department of Cell and Molecular BiologyUniversity of Mississippi Medical CenterJacksonMississippi
| | - Kiran Chandrashekar
- Department of Medicine/NephrologyCentral Arkansas Veterans Healthcare SystemUniversity of Arkansas for Medical SciencesLittle RockArkansas
| | | | - Guillermo B. Silva
- Department of Basic ResearchJ. Robert Cade FoundationCordobaArgentina
- Gabinete de Tecnología Médica (GATEME‐UNSJ)Universidad Nacional de San Juan ‐ Consejo Nacional de Investigaciones Científicas y Técnicas – CONICETSan JuanArgentina
| | - Luis A. Juncos
- Department of Medicine/NephrologyCentral Arkansas Veterans Healthcare SystemUniversity of Arkansas for Medical SciencesLittle RockArkansas
| | - Luis I. Juncos
- Department of Basic ResearchJ. Robert Cade FoundationCordobaArgentina
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35
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South AM, Shaltout HA, Washburn LK, Hendricks AS, Diz DI, Chappell MC. Fetal programming and the angiotensin-(1-7) axis: a review of the experimental and clinical data. Clin Sci (Lond) 2019; 133:55-74. [PMID: 30622158 PMCID: PMC6716381 DOI: 10.1042/cs20171550] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 11/20/2018] [Accepted: 12/03/2018] [Indexed: 02/07/2023]
Abstract
Hypertension is the primary risk factor for cardiovascular disease that constitutes a serious worldwide health concern and a significant healthcare burden. As the majority of hypertension has an unknown etiology, considerable research efforts in both experimental models and human cohorts has focused on the premise that alterations in the fetal and perinatal environment are key factors in the development of hypertension in children and adults. The exact mechanisms of how fetal programming events increase the risk of hypertension and cardiovascular disease are not fully elaborated; however, the focus on alterations in the biochemical components and functional aspects of the renin-angiotensin (Ang) system (RAS) has predominated, particularly activation of the Ang-converting enzyme (ACE)-Ang II-Ang type 1 receptor (AT1R) axis. The emerging view of alternative pathways within the RAS that may functionally antagonize the Ang II axis raise the possibility that programming events also target the non-classical components of the RAS as an additional mechanism contributing to the development and progression of hypertension. In the current review, we evaluate the potential role of the ACE2-Ang-(1-7)-Mas receptor (MasR) axis of the RAS in fetal programming events and cardiovascular and renal dysfunction. Specifically, the review examines the impact of fetal programming on the Ang-(1-7) axis within the circulation, kidney, and brain such that the loss of Ang-(1-7) expression or tone, contributes to the chronic dysregulation of blood pressure (BP) and cardiometabolic disease in the offspring, as well as the influence of sex on potential programming of this pathway.
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Affiliation(s)
- Andrew M South
- Department of Pediatrics, Section of Nephrology, Wake Forest School of Medicine, 526 Vine Street, Winston Salem, NC 27157, U.S.A
- Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, 526 Vine Street, Winston Salem, NC 27157, U.S.A
- Cardiovascular Sciences Center, Wake Forest School of Medicine, 526 Vine Street, Winston Salem, NC 27157, U.S.A
- Hypertension and Vascular Research, Wake Forest School of Medicine, 526 Vine Street, Winston Salem, NC 27157, U.S.A
| | - Hossam A Shaltout
- Cardiovascular Sciences Center, Wake Forest School of Medicine, 526 Vine Street, Winston Salem, NC 27157, U.S.A
- Department of Obstetrics and Gynecology, Wake Forest School of Medicine, 526 Vine Street, Winston Salem, NC 27157, U.S.A
- Department of Pharmacology and Toxicology, School of Pharmacy, University of Alexandria, Egypt
- Hypertension and Vascular Research, Wake Forest School of Medicine, 526 Vine Street, Winston Salem, NC 27157, U.S.A
- Department of Surgery, Wake Forest School of Medicine, 526 Vine Street, Winston Salem, NC 27157, U.S.A
| | - Lisa K Washburn
- Department of Pediatrics, Section of Nephrology, Wake Forest School of Medicine, 526 Vine Street, Winston Salem, NC 27157, U.S.A
- Cardiovascular Sciences Center, Wake Forest School of Medicine, 526 Vine Street, Winston Salem, NC 27157, U.S.A
- Hypertension and Vascular Research, Wake Forest School of Medicine, 526 Vine Street, Winston Salem, NC 27157, U.S.A
| | - Alexa S Hendricks
- Cardiovascular Sciences Center, Wake Forest School of Medicine, 526 Vine Street, Winston Salem, NC 27157, U.S.A
- Hypertension and Vascular Research, Wake Forest School of Medicine, 526 Vine Street, Winston Salem, NC 27157, U.S.A
| | - Debra I Diz
- Cardiovascular Sciences Center, Wake Forest School of Medicine, 526 Vine Street, Winston Salem, NC 27157, U.S.A
- Hypertension and Vascular Research, Wake Forest School of Medicine, 526 Vine Street, Winston Salem, NC 27157, U.S.A
- Department of Surgery, Wake Forest School of Medicine, 526 Vine Street, Winston Salem, NC 27157, U.S.A
| | - Mark C Chappell
- Cardiovascular Sciences Center, Wake Forest School of Medicine, 526 Vine Street, Winston Salem, NC 27157, U.S.A.
- Hypertension and Vascular Research, Wake Forest School of Medicine, 526 Vine Street, Winston Salem, NC 27157, U.S.A
- Department of Surgery, Wake Forest School of Medicine, 526 Vine Street, Winston Salem, NC 27157, U.S.A
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Guignabert C, de Man F, Lombès M. ACE2 as therapy for pulmonary arterial hypertension: the good outweighs the bad. Eur Respir J 2018; 51:51/6/1800848. [PMID: 29929959 DOI: 10.1183/13993003.00848-2018] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 05/09/2018] [Indexed: 01/20/2023]
Affiliation(s)
- Christophe Guignabert
- INSERM UMR_S 999, Hôpital Marie Lannelongue, Le Plessis-Robinson, France.,Faculté de Médecine, Université Paris-Sud and Université Paris Saclay, Le Kremlin-Bicêtre, France
| | - Frances de Man
- Dept of Pulmonology, Amsterdam Cardiovascular Sciences, VU University Medical Center, Amsterdam, The Netherlands
| | - Marc Lombès
- Faculté de Médecine, Université Paris-Sud and Université Paris Saclay, Le Kremlin-Bicêtre, France.,INSERM UMR_S 1185, Le Kremlin-Bicêtre, France.,Service d'Endocrinologie et des Maladies de la Reproduction, Hôpitaux Universitaires Paris-Sud, CHU Bicêtre, AH-HP, Le Kremlin Bicêtre, France
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37
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Identification of protein phosphatase involvement in the AT 2 receptor-induced activation of endothelial nitric oxide synthase. Clin Sci (Lond) 2018. [PMID: 29540539 DOI: 10.1042/cs20171598] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
The Angiotensin II type 2 receptor (AT2R) promotes vasodilation by nitric oxide (NO) release from endothelial cells. However, the mechanisms underlying the AT2R-induced stimulation of endothelial NO synthase (eNOS) is still not completely understood. Therefore, we investigated whether in addition to the known AT2R-mediated phosphorylation of eNOS at Ser1177, activation of phosphatases and dephosphorylation of eNOS at Tyr657 and Thr495 are also involved. Human aortic endothelial cells (HAEC) were stimulated with the AT2R-agonist Compound 21 (C21) (1 µM) in the presence or absence of either PD123319 (10 µM; AT2R antagonist), l-NG-Nitroarginine methyl ester (l-NAME) (10 µM; eNOS inhibitor), MK-2206 (100 nM; protein kinase B (Akt) inhibitor) sodium fluoride (NaF) (1 nM; serine/threonine phosphatase inhibitor) or sodium orthovanadate (Na3VO4) (10 nM; tyrosine phosphatase inhibitor). NO release was estimated by quantifying 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate (DAF-FM) fluorescence. The phosphorylation status of activating (eNOS-Ser1177) or inhibitory eNOS residues (eNOS-Tyr657, eNOS-Thr495) was determined by Western blotting. Phosphorylation of Akt at Ser473 was measured to estimate Akt activity. AT2R stimulation significantly increased NO release from HAEC, which was blocked by PD123319, l-NAME and both phosphatase inhibitors. Intracellular calcium transients were not changed by C21. AT2R stimulation resulted in phosphorylation of eNOS-Ser1177 and dephosphorylation of eNOS-Tyr657 and eNOS-Thr495 Phosphorylation at eNOS-Ser1177 was prevented by inhibition of Akt with MK-2206. From these data, we conclude that AT2R stimulation in human endothelial cells increases eNOS activity through phosphorylation of activating eNOS residues (eNOS-Ser1177) by Akt, and through dephosphorylation of inactivating eNOS residues (eNOS-Tyr657, eNOS-Thr495) by serine/threonine and tyrosine phosphatases, thus increasing NO release.
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38
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Maleki M, Hasanshahi J, Moslemi F. The Role of Vasodilator Receptors of Renin-angiotensin System on Nitric Oxide Formation and Kidney Circulation after Angiotensin II Infusion in Renal Ischemia/Reperfusion Rats. Adv Biomed Res 2018. [PMID: 29531923 PMCID: PMC5841005 DOI: 10.4103/2277-9175.225596] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background: Nitric oxide (NO) as a vasodilator factor has renoprotective effect against renal ischemia. The balance between angiotensin II (Ang II) and NO can affect kidney homeostasis. The aim of this study was to determine NO alteration in response to renin–Ang system vasodilator receptors antagonists (PD123319; Ang II type 2 receptor antagonist and A779; Mas receptor antagonist) in renal ischemia/reperfusion injury (IRI) in rats. Materials and Methods: Sixty-three Wistar male and female rats were used. Animals from each gender were divided into four groups received saline, Ang II, PD123319 + Ang II, and A779 + Ang II after renal IRI. Renal IRI induced with an adjustable hook. Blood pressure and renal blood flow (RBF) measured continuously. The nitrite levels were measured in serum, kidney, and urine samples. Results: In female rats, the serum and kidney nitrite levels increased significantly by Ang II (P < 0.05) and decreased significantly (P < 0.05) when PD123319 was accompanied with Ang II. Such observation was not seen in male. Ang II decreased RBF significantly in all groups (P < 0.05), while PD + Ang II group showed significant decrease in RBF in comparison with the other groups in female rats (P < 0.05). Conclusion: Males show more sensibility to Ang II infusion; in fact, it is suggested that there is gender dimorphism in the Ang II and NO production associated with vasodilator receptors.
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Affiliation(s)
- Maryam Maleki
- Water and Electrolytes Research Center/Department of Physiology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Jalal Hasanshahi
- Water and Electrolytes Research Center/Department of Physiology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fatemeh Moslemi
- Water and Electrolytes Research Center/Department of Physiology, Isfahan University of Medical Sciences, Isfahan, Iran
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Higaki A, Mogi M, Iwanami J, Min LJ, Bai HY, Shan BS, Kukida M, Yamauchi T, Tsukuda K, Kan-No H, Ikeda S, Higaki J, Horiuchi M. Beneficial Effect of Mas Receptor Deficiency on Vascular Cognitive Impairment in the Presence of Angiotensin II Type 2 Receptor. J Am Heart Assoc 2018; 7:JAHA.117.008121. [PMID: 29431106 PMCID: PMC5850265 DOI: 10.1161/jaha.117.008121] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND The classical renin-angiotensin system is known as the angiotensin (Ang)-converting enzyme/Ang II/Ang type 1 receptor axis, which induces various organ damage including cognitive decline. The angiotensin-converting enzyme 2/Ang-(1-7)/Mas axis is known to exert antagonistic actions against the classical renin-angiotensin system axis in the cardiovascular system. However, its roles in the brain remain unclear. We examined possible roles of the angiotensin-converting enzyme 2/Ang-(1-7)/Mas axis in cognitive function, employing vascular cognitive impairment model mice. METHODS AND RESULTS Male 10-week-old C57BL6 (wild-type mice, Mas1 knockout mice, Ang II type 2 receptor knockout mice, and Ang II type 2 receptor/Mas1 double knockout mice were subjected to bilateral carotid artery stenosis (BCAS) surgery. Six weeks after treatment, they were subjected to cognitive tasks. Brain samples were used for histopathological analysis. Cognitive function was significantly impaired in wild-type and double knockout mice after BCAS. On the other hand, the cognitive function of Mas1 knockout mice was maintained in spite of the reduction of cerebral blood flow with BCAS. Total cell number in the dentate gyrus region was significantly reduced after BCAS in wild-type but not in Mas1 knockout mice. The number of doublecortin-positive cells in the subgranular zone was not significantly different between wild-type and Mas1 knockout mice. Ang-(1-7) administration did not improve cognitive function in all mice after BCAS surgery. CONCLUSIONS Lack of the Mas receptor may have a protective effect against chronic brain ischemia when the Ang II type 2 receptor exists.
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Affiliation(s)
- Akinori Higaki
- Department of Molecular Cardiovascular Biology and Pharmacology, Graduate School of Medicine, Ehime University, Tohon, Ehime, Japan.,Department of Cardiology, Pulmonology, Hypertension and Nephrology, Graduate School of Medicine, Ehime University, Tohon, Ehime, Japan
| | - Masaki Mogi
- Department of Molecular Cardiovascular Biology and Pharmacology, Graduate School of Medicine, Ehime University, Tohon, Ehime, Japan
| | - Jun Iwanami
- Department of Molecular Cardiovascular Biology and Pharmacology, Graduate School of Medicine, Ehime University, Tohon, Ehime, Japan
| | - Li-Juan Min
- Department of Molecular Cardiovascular Biology and Pharmacology, Graduate School of Medicine, Ehime University, Tohon, Ehime, Japan
| | - Hui-Yu Bai
- Department of Molecular Cardiovascular Biology and Pharmacology, Graduate School of Medicine, Ehime University, Tohon, Ehime, Japan
| | - Bao-Shuai Shan
- Department of Molecular Cardiovascular Biology and Pharmacology, Graduate School of Medicine, Ehime University, Tohon, Ehime, Japan
| | - Masayoshi Kukida
- Department of Molecular Cardiovascular Biology and Pharmacology, Graduate School of Medicine, Ehime University, Tohon, Ehime, Japan.,Department of Cardiology, Pulmonology, Hypertension and Nephrology, Graduate School of Medicine, Ehime University, Tohon, Ehime, Japan
| | - Toshifumi Yamauchi
- Department of Pediatrics, Graduate School of Medicine, Ehime University, Tohon, Ehime, Japan
| | - Kana Tsukuda
- Department of Molecular Cardiovascular Biology and Pharmacology, Graduate School of Medicine, Ehime University, Tohon, Ehime, Japan
| | - Harumi Kan-No
- Department of Molecular Cardiovascular Biology and Pharmacology, Graduate School of Medicine, Ehime University, Tohon, Ehime, Japan
| | - Shuntaro Ikeda
- Department of Cardiology, Pulmonology, Hypertension and Nephrology, Graduate School of Medicine, Ehime University, Tohon, Ehime, Japan
| | - Jitsuo Higaki
- Department of Cardiology, Pulmonology, Hypertension and Nephrology, Graduate School of Medicine, Ehime University, Tohon, Ehime, Japan
| | - Masatsugu Horiuchi
- Department of Molecular Cardiovascular Biology and Pharmacology, Graduate School of Medicine, Ehime University, Tohon, Ehime, Japan
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40
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Brenner JS, Kiseleva RY, Glassman PM, Parhiz H, Greineder CF, Hood ED, Shuvaev VV, Muzykantov VR. The new frontiers of the targeted interventions in the pulmonary vasculature: precision and safety (2017 Grover Conference Series). Pulm Circ 2017; 8:2045893217752329. [PMID: 29261028 PMCID: PMC5768280 DOI: 10.1177/2045893217752329] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The pulmonary vasculature plays an important role in many lung pathologies, such as pulmonary arterial hypertension, primary graft dysfunction of lung transplant, and acute respiratory distress syndrome. Therapy for these diseases is quite limited, largely due to dose-limiting side effects of numerous drugs that have been trialed or approved. High doses of drugs targeting the pulmonary vasculature are needed due to the lack of specific affinity of therapeutic compounds to the vasculature. To overcome this problem, the field of targeted drug delivery aims to target drugs to the pulmonary endothelial cells, especially those in pathological regions. The field uses a variety of drug delivery systems (DDSs), ranging from nano-scale drug carriers, such as liposomes, to methods of conjugating drugs to affinity moieites, such as antibodies. These DDSs can deliver small molecule drugs, protein therapeutics, and imaging agents. Here we review targeted drug delivery to the pulmonary endothelium for the treatment of pulmonary diseases. Cautionary notes are made of the risk–benefit ratio and safety—parameters one should keep in mind when developing a translational therapeutic.
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Affiliation(s)
- Jacob S Brenner
- 1 14640 Pulmonary, Allergy, & Critical Care Division, University of Pennsylvania, Philadelphia, PA, USA
| | - Raisa Yu Kiseleva
- 2 14640 Department of Pharmacology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Patrick M Glassman
- 2 14640 Department of Pharmacology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Hamideh Parhiz
- 2 14640 Department of Pharmacology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Colin F Greineder
- 2 14640 Department of Pharmacology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Elizabeth D Hood
- 2 14640 Department of Pharmacology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Vladimir V Shuvaev
- 2 14640 Department of Pharmacology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Vladimir R Muzykantov
- 2 14640 Department of Pharmacology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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41
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Lin S, Pan H, Wu H, Ren D, Lu J. Role of the ACE2‑Ang‑(1‑7)‑Mas axis in blood pressure regulation and its potential as an antihypertensive in functional foods (Review). Mol Med Rep 2017; 16:4403-4412. [PMID: 28791402 DOI: 10.3892/mmr.2017.7168] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 06/08/2017] [Indexed: 11/05/2022] Open
Abstract
The renin‑angiotensin system (RAS) serves a critical role in blood pressure regulation and prevention of cardiovascular diseases. Efforts to develop functional foods that enhance the RAS have focused on inhibition of angiotensin‑converting enzyme (ACE) activity in the ACE‑angiotensin II (Ang II)‑Ang II type 1 receptor axis. ACE2 and the Mas receptor are important components of this axis. ACE2 catalyzes Ang II into Ang‑(1‑7), which then binds to the G‑protein‑coupled receptor Mas. In addition, it induces nitric oxide release from endothelial cells and exerts antiproliferative, vasodilatory and antihypertensive effects. The present review examined recent findings regarding the physiological and biological roles of the ACE2‑Ang‑(1‑7)‑Mas axis in the cardiovascular system, discussed potential food‑derived ACE2‑activating agents, and highlighted initiatives, based on this axis, that aim to develop functional foods for the treatment of hypertension.
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Affiliation(s)
- Shiqi Lin
- Beijing Key Laboratory of Forest Food Process and Safety, Department of Food Science and Engineering, College of Biological Sciences and Technology, Beijing Forestry University, Beijing 100083, P.R. China
| | - Huanglei Pan
- Beijing Key Laboratory of Forest Food Process and Safety, Department of Food Science and Engineering, College of Biological Sciences and Technology, Beijing Forestry University, Beijing 100083, P.R. China
| | - Hongli Wu
- Beijing Key Laboratory of Forest Food Process and Safety, Department of Food Science and Engineering, College of Biological Sciences and Technology, Beijing Forestry University, Beijing 100083, P.R. China
| | - Difeng Ren
- Beijing Key Laboratory of Forest Food Process and Safety, Department of Food Science and Engineering, College of Biological Sciences and Technology, Beijing Forestry University, Beijing 100083, P.R. China
| | - Jun Lu
- Beijing Engineering Research Center of Protein and Functional Peptides, China National Research Institute of Food and Fermentation Industries, Beijing 100015, P.R. China
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42
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Yousif MHM, Benter IF, Diz DI, Chappell MC. Angiotensin-(1-7)-dependent vasorelaxation of the renal artery exhibits unique angiotensin and bradykinin receptor selectivity. Peptides 2017; 90:10-16. [PMID: 28192151 PMCID: PMC6688182 DOI: 10.1016/j.peptides.2017.02.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Revised: 12/23/2016] [Accepted: 02/03/2017] [Indexed: 01/31/2023]
Abstract
Angiotensin-(1-7) [Ang-(1-7)] exhibits blood pressure lowering actions, inhibits cell growth, and reduces tissue inflammation and fibrosis which may functionally antagonize an activated Ang II-AT1 receptor axis. Since the vascular actions of Ang-(1-7) and the associated receptor/signaling pathways vary in different vascular beds, the current study established the vasorelaxant properties of the heptapeptide in the renal artery of male Wistar male rats. Ang-(1-7) produced an endothelium-dependent vasodilator relaxation of isolated renal artery segments pre-contracted by a sub-maximal concentration of phenylephrine (PE) (3×10-7M). Ang-(1-7) induced vasodilation of the rat renal artery with an ED50 of 3±1nM and a maximal response of 42±5% (N=10). The two antagonists (10-5M each) for the AT7/Mas receptor (MasR) [D-Pro7]-Ang-(1-7) and [D-Ala7]-Ang-(1-7) significantly reduced the maximal response to 12±1% and 18±3%, respectively. Surprisingly, the AT2R receptor antagonist PD123319, the AT1R antagonist losartan and B2R antagonist HOE140 (10-6M each) also significantly reduced Ang-(1-7)-induced relaxation to 12±2%, 22±3% and 14±7%, respectively. Removal of the endothelium or addition of the soluble guanylate cyclase (sGC) inhibitor ODQ (10-5M) essentially abolished the vasorelaxant response to Ang-(1-7) (10±4% and 10±2%, P <0.05). Finally, the NOS inhibitor LNAME (10-4M) reduced the response to 13±2% (p<0.05), but the cyclooxygenase inhibitor indomethacin failed to block the Ang-(1-7) response. We conclude that Ang-(1-7) exhibits potent vasorelaxant actions in the isolated renal artery that are dependent on an intact endothelium and the apparent stimulation of a NO-sGC pathway. Moreover, Ang-(1-7)-dependent vasorelaxation was sensitive to antagonists against the AT7/Mas, AT1, AT2 and B2 receptor subtypes.
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Affiliation(s)
- Mariam H M Yousif
- Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, Kuwait
| | - Ibrahim F Benter
- Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, Kuwait
| | - Debra I Diz
- The Hypertension & Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Mark C Chappell
- The Hypertension & Vascular Research Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
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43
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Endlich PW, Claudio ERG, Lima LCF, Ribeiro Júnior RF, Peluso AAB, Stefanon I, Bissoli NS, Lemos VS, Santos RASD, Abreu GRD. Exercise modulates the aortic renin-angiotensin system independently of estrogen therapy in ovariectomized hypertensive rats. Peptides 2017; 87:41-49. [PMID: 27884622 DOI: 10.1016/j.peptides.2016.11.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Revised: 11/15/2016] [Accepted: 11/21/2016] [Indexed: 01/08/2023]
Abstract
The renin-angiotensin-system is an important component of cardiovascular control and is up-regulated under various conditions, including hypertension and menopause. The aim of this study was to evaluate the effects of swimming training and estrogen therapy (ET) on angiotensin-II (ANG II)-induced vasoconstriction and angiotensin-(1-7) [ANG-(1-7)]-induced vasorelaxation in aortic rings from ovariectomized spontaneously hypertensive rats. Animals were divided into Sham (SH), Ovariectomized (OVX), Ovariectomized treated with E2 (OE2), Ovariectomized plus swimming (OSW) and Ovariectomized treated with E2 plus swimming (OE2+SW) groups. ET entailed the administration of 5μg of 17β-Estradiol three times per week. Swimming was undertaken for sixty minutes each day, five times per week. Both, training and ET were initiated seven days following ovariectomy. Forty-eight hours after the last treatment or training session, the animals' systolic blood pressures were measured, and blood samples were collected to measure plasma ANG II and ANG-(1-7) levels via radioimmunoassay. In aortic rings, the vascular reactivity to ANG II and ANG-(1-7) was assessed. Expression of ANG-(1-7) in aortic wall was analyzed by immunohistochemistry. The results showed that both exercise and ET increased plasma ANG II levels despite attenuating systolic blood pressure. Ovariectomy increased constrictor responses to ANG II and decreased dilatory responses to ANG-(1-7), which were reversed by swimming independently of ET. Moreover, it was observed an apparent increase in ANG-(1-7) content in the aorta of the groups subjected to training and ET. Exercise training may play a cardioprotective role independently of ET and may be an alternative to ET in hypertensive postmenopausal women.
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Affiliation(s)
- Patrick W Endlich
- Department of Physiological Sciences, Health Sciences Center, Federal University of Espírito Santo, Vitoria, ES, Brazil; Programa Multicêntrico de Pós-Graduação em Ciências Fisiológicas, Federal University of Valleys of Jequitinhonha and Mucuri, Teófilo Otoni, MG, Brazil
| | - Erick R G Claudio
- Department of Physiological Sciences, Health Sciences Center, Federal University of Espírito Santo, Vitoria, ES, Brazil
| | - Leandro C F Lima
- Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Rogério F Ribeiro Júnior
- Department of Physiological Sciences, Health Sciences Center, Federal University of Espírito Santo, Vitoria, ES, Brazil
| | - Antonio A B Peluso
- Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Ivanita Stefanon
- Department of Physiological Sciences, Health Sciences Center, Federal University of Espírito Santo, Vitoria, ES, Brazil
| | - Nazaré S Bissoli
- Department of Physiological Sciences, Health Sciences Center, Federal University of Espírito Santo, Vitoria, ES, Brazil
| | - Virginia S Lemos
- Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Robson A S Dos Santos
- Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Glaucia R de Abreu
- Department of Physiological Sciences, Health Sciences Center, Federal University of Espírito Santo, Vitoria, ES, Brazil.
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Raffai G, Lombard JH. Angiotensin-(1-7) Selectively Induces Relaxation and Modulates Endothelium-Dependent Dilation in Mesenteric Arteries of Salt-Fed Rats. J Vasc Res 2016; 53:105-118. [PMID: 27676088 DOI: 10.1159/000448714] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 07/26/2016] [Indexed: 12/19/2022] Open
Abstract
This study investigated the acute effects of angiotensin-(1-7) and AVE0991 on active tone and vasodilator responses to bradykinin and acetylcholine in isolated mesenteric arteries from Sprague-Dawley rats fed a high-salt (HS; 4% NaCl) versus a normal salt (NS; 0.4% NaCl) diet. Angiotensin-(1-7) and AVE0991 elicited relaxation, and angiotensin-(1-7) unmasked vasodilator responses to bradykinin in arteries from HS-fed rats. These effects of angiotensin-(1-7) and AVE0991 were inhibited by endothelium removal, A779, PD123319, HOE140 and L-NAME. Angiotensin-(1-7) also restored the acetylcholine-induced relaxation that was suppressed by the HS diet. Vasodilator responses to bradykinin and acetylcholine in the presence of angiotensin-(1-7) were mimicked by captopril and the AT2 receptor agonist CGP42112 in arteries from HS-fed rats. Thus, in contrast to salt-induced impairment of vascular relaxation in response to vasodilator stimuli, angiotensin-(1-7) induces endothelium-dependent and NO-mediated relaxation, unmasks bradykinin responses via activation of mas and AT2 receptors, and restores acetylcholine-induced vasodilation in HS-fed rats. AT2 receptor activation and angiotensin-converting enzyme (ACE) inhibition shared the ability of angiotensin-(1-7) to enhance bradykinin and acetylcholine responses in HS-fed rats. These findings suggest a therapeutic potential for mas and/or AT2 receptor activation and ACE inhibition in restoring endothelial function impaired by elevated dietary salt intake or other pathological conditions.
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Affiliation(s)
- Gábor Raffai
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wis., USA
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45
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Maleki M, Nematbakhsh M. Renal Blood Flow Response to Angiotensin 1-7 versus Hypertonic Sodium Chloride 7.5% Administration after Acute Hemorrhagic Shock in Rats. Int J Vasc Med 2016; 2016:6562017. [PMID: 27073699 PMCID: PMC4814681 DOI: 10.1155/2016/6562017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Revised: 02/04/2016] [Accepted: 02/17/2016] [Indexed: 11/24/2022] Open
Abstract
Background. Angiotensin 1-7 (Ang1-7) plays an important role in renal circulation. Hemorrhagic shock (HS) may cause kidney circulation disturbance, and this study was designed to investigate the renal blood flow (RBF) response to Ang1-7 after HS. Methods. 27 male Wistar rats were subjected to blood withdrawal to reduce mean arterial pressure (MAP) to 45 mmHg for 45 min. The animals were treated with saline (group 1), Ang1-7 (300 ng·kg(-1) min(-1)), Ang1-7 in hypertonic sodium chloride 7.5% (group 3), and hypertonic solution alone (group 4). Results. MAP was increased in a time-related fashion (P time < 0.0001) in all groups; however, there was a tendency for the increase in MAP in response to hypertonic solution (P = 0.09). Ang1-7, hypertonic solution, or combination of both increased RBF in groups 2-4, and these were significantly different from saline group (P = 0.05); that is, Ang1-7 leads to a significant increase in RBF to 1.35 ± 0.25 mL/min compared with 0.55 ± 0.12 mL/min in saline group (P < 0.05). Conclusion. Although Ang1-7 administration unlike hypertonic solution could not elevate MAP after HS, it potentially could increase RBF similar to hypertonic solution. This suggested that Ang1-7 recovers RBF after HS when therapeutic opportunities of hypertonic solution are limited.
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Affiliation(s)
- Maryam Maleki
- Water and Electrolytes Research Center, Isfahan University of Medical Sciences, Isfahan 81745, Iran
| | - Mehdi Nematbakhsh
- Water and Electrolytes Research Center, Isfahan University of Medical Sciences, Isfahan 81745, Iran; Department of Physiology, Isfahan University of Medical Sciences, Isfahan 81745, Iran; Isfahan MN Institute of Basic and Applied Sciences Research, Isfahan 81745, Iran
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Sindone A, Erlich J, Lee C, Newman H, Suranyi M, Roger SD. Cardiovascular risk reduction in hypertension: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers. Where are we up to? Intern Med J 2016; 46:364-72. [DOI: 10.1111/imj.12975] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2015] [Revised: 11/05/2015] [Accepted: 11/16/2015] [Indexed: 11/26/2022]
Affiliation(s)
- A. Sindone
- Heart Failure Unit and Department of Cardiac Rehabilitation; Concord Repatriation General Hospital; Concord New South Wales Australia
| | - J. Erlich
- Faculty of Medicine; University of NSW; Sydney New South Wales Australia
- Department of Nephrology; Prince of Wales Hospital; Sydney New South Wales Australia
| | - C. Lee
- Department of Cardiology; Nepean Hospital; Sydney New South Wales Australia
| | - H. Newman
- Department of Cardiology; Liverpool Hospital; Sydney New South Wales Australia
| | - M. Suranyi
- Liverpool Renal Clinical Research Centre; Liverpool Hospital; Sydney New South Wales Australia
| | - S. D. Roger
- Department of Renal Medicine; Gosford Hospital; Gosford New South Wales Australia
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Neuroprotective mechanisms of the ACE2-angiotensin-(1-7)-Mas axis in stroke. Curr Hypertens Rep 2016; 17:3. [PMID: 25620630 DOI: 10.1007/s11906-014-0512-2] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The discovery of beneficial neuroprotective effects of the angiotensin converting enzyme 2-angiotensin-(1-7)-Mas axis [ACE2-Ang-(1-7)-Mas] in ischemic and hemorrhagic stroke has spurred interest in a more complete characterization of its mechanisms of action. Here, we summarize findings that describe the protective role of the ACE2-Ang-(1-7)-Mas axis in stroke, along with a focused discussion on the potential mechanisms of neuroprotective effects of Ang-(1-7) in stroke. The latter incorporates evidence describing the actions of Ang-(1-7) to counter the deleterious effects of angiotensin II (AngII) via its type 1 receptor, including anti-inflammatory, anti-oxidant, vasodilatory, and angiogenic effects, and the role of altered kinase-phosphatase signaling. Interactions of Mas with other receptors, including bradykinin receptors and AngII type 2 receptors are also considered. A more complete understanding of the mechanisms of action of Ang-(1-7) to elicit neuroprotection will serve as an essential step toward research into potential targeted therapeutics in the clinical setting.
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48
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Ohira H. Spleen and Liver. THE LIVER IN SYSTEMIC DISEASES 2016. [PMCID: PMC7122130 DOI: 10.1007/978-4-431-55790-6_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
In liver cirrhosis, the spleen is a source of nitric oxide which affects a hyperdynamic state typical of portal hypertension. It is generally accepted that pancytopenia results predominantly from the increased phagocytosis and destruction of hemocytes in splenic macrophages. In addition, liver fibrosis is amplified by migrated Th2 lymphocytes and transforming growth factor beta from the spleen. There is a possibility that increase of the spleen stiffness is the primary factor of idiopathic portal hypertension. Spleen stiffness is caused by bleeding, fibrosis, and calcareous deposits after increase in red pulp pressure due to venous congestion. In nonalcoholic steatohepatitis, macrophage activity in the spleen is upregulated. In addition, high levels of inflammatory cytokines are produced and T cell shows increased proliferation in the spleen. In autoimmune hepatitis model, CD4+ T cells are differentiated into follicular helper T cells (TFH) in the spleen. TFH cells promoted hypergammaglobulinemia and antinuclear antibodies production. TFH cells migrate from the spleen to the liver, triggering induction of autoimmune hepatitis in this model. IgM-positive B cells localize in the CD21-positive lymph follicle in the spleen of primary biliary cholangitis. These findings prove that the spleen influences on the pathogenesis and severity of several kinds of liver disease.
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Affiliation(s)
- Hiromasa Ohira
- Dept. Gastroenterology & Rheumatogy, Fukushima Med. Univ. School of Med., Fukushima, Fukushima Japan
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Breitling S, Krauszman A, Parihar R, Walther T, Friedberg MK, Kuebler WM. Dose-dependent, therapeutic potential of angiotensin-(1-7) for the treatment of pulmonary arterial hypertension. Pulm Circ 2015; 5:649-57. [PMID: 26697172 DOI: 10.1086/683696] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The effects of the heptapeptide angiotensin-(1-7) (Ang-(1-7)), via its receptor Mas, oppose many of the effects of the classic angiotensin II signaling pathway, and pharmacological exploitation of this effect is currently actively pursued for a wide range of cardiovascular, neoplastic, or immunological disorders. On the basis of its vasodilatory and antiproliferative properties, Ang-(1-7) has consequentially also been proposed as a novel therapeutic strategy for the treatment of pulmonary arterial hypertension (PAH). In this study, we tested the effectiveness of Ang-(1-7) and its stable, cyclic analog cAng-(1-7) over a range of doses for their therapeutic potential in experimental PAH. In the monocrotaline (MCT) rat model of PAH, Ang-(1-7) or cAng-(1-7) were injected in doses of 30, 100, 300, or 900 μg kg(-1) day(-1), and effects on pulmonary hemodynamics and vascular remodeling were assessed. Five weeks after MCT injection, right ventricular systolic pressure (RVSP) was significantly reduced for 3 dose groups treated with Ang-(1-7) (100, 300, and 900 μg kg(-1) day(-1)) and for all dose groups treated with cAng-(1-7), as compared to untreated controls, yet the total reduction of RVSP was <50% at best and thus markedly lower than that with a positive treatment control with ambrisentan. Medial-wall thickness in pulmonary arterioles was only slightly reduced, without reaching significance, for any of the tested Ang-(1-7) compounds and doses. The reported moderate attenuation of PAH does not confirm the previously postulated high promise of this strategy, and the therapeutic usefulness of Ang-(1-7) may be limited in PAH relative to that in other cardiovascular diseases.
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Affiliation(s)
- Siegfried Breitling
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada ; Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
| | - Adrienn Krauszman
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada ; Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Richa Parihar
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Thomas Walther
- Department of Pharmacology and Therapeutics, School of Medicine, School of Pharmacy, University College Cork, Cork, Ireland
| | - Mark K Friedberg
- Labatt Family Heart Center, Division of Cardiology and Cardiovascular Surgery, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada
| | - Wolfgang M Kuebler
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada ; Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany ; Departments of Surgery and Physiology, University of Toronto, Toronto, Ontario, Canada; and German Heart Institute Berlin, Berlin, Germany
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50
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Boegehold MA, Drenjancevic I, Lombard JH. Salt, Angiotensin II, Superoxide, and Endothelial Function. Compr Physiol 2015; 6:215-54. [PMID: 26756632 DOI: 10.1002/cphy.c150008] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Proper function of the vascular endothelium is essential for cardiovascular health, in large part due to its antiproliferative, antihypertrophic, and anti-inflammatory properties. Crucial to the protective role of the endothelium is the production and liberation of nitric oxide (NO), which not only acts as a potent vasodilator, but also reduces levels of reactive oxygen species, including superoxide anion (O2•-). Superoxide anion is highly injurious to the vasculature because it not only scavenges NO molecules, but has other damaging effects, including direct oxidative disruption of normal signaling mechanisms in the endothelium and vascular smooth muscle cells. The renin-angiotensin system plays a crucial role in the maintenance of normal blood pressure. This function is mediated via the peptide hormone angiotensin II (ANG II), which maintains normal blood volume by regulating Na+ excretion. However, elevation of ANG II above normal levels increases O2•- production, promotes oxidative stress and endothelial dysfunction, and plays a major role in multiple disease conditions. Elevated dietary salt intake also leads to oxidant stress and endothelial dysfunction, but these occur in the face of salt-induced ANG II suppression and reduced levels of circulating ANG II. While the effects of abnormally high levels of ANG II have been extensively studied, far less is known regarding the mechanisms of oxidant stress and endothelial dysfunction occurring in response to chronic exposure to abnormally low levels of ANG II. The current article focuses on the mechanisms and consequences of this less well understood relationship among salt, superoxide, and endothelial function.
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Affiliation(s)
| | - Ines Drenjancevic
- Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| | - Julian H Lombard
- Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
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