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Liu LP, Zhang XL, Li J. New perspectives on angiotensin-converting enzyme 2 and its related diseases. World J Diabetes 2021; 12:839-854. [PMID: 34168732 PMCID: PMC8192247 DOI: 10.4239/wjd.v12.i6.839] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/30/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
Since the worldwide outbreak of coronavirus disease 2019, angiotensin-converting enzyme 2 (ACE2) has received widespread attention as the cell receptor of the severe acute respiratory syndrome coronavirus 2 virus. At the same time, as a key enzyme in the renin-angiotensin-system, ACE2 is considered to be an endogenous negative regulator of vasoconstriction, proliferation, fibrosis, and proinflammation caused by the ACE-angiotensin II-angiotensin type 1 receptor axis. ACE2 is now implicated as being closely connected to diabetes, cardiovascular, kidney, and lung diseases, and so on. This review covers the available information on the host factors regulating ACE2 and discusses its role in a variety of pathophysiological conditions in animal models and humans.
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Affiliation(s)
- Li-Ping Liu
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, School of Medicine, Hunan Normal University, Changsha 410013, Hunan Province, China
| | - Xiao-Li Zhang
- TheFifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg 68135, Baden-Württemberg, Germany
| | - Jian Li
- Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, School of Medicine, Hunan Normal University, Changsha 410013, Hunan Province, China
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De Lange-Jacobs P, Shaikh-Kader A, Thomas B, Nyakudya TT. An Overview of the Potential Use of Ethno-Medicinal Plants Targeting the Renin-Angiotensin System in the Treatment of Hypertension. Molecules 2020; 25:E2114. [PMID: 32366012 PMCID: PMC7249071 DOI: 10.3390/molecules25092114] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 04/15/2020] [Accepted: 04/22/2020] [Indexed: 01/09/2023] Open
Abstract
The development of risk factors associated with cardiovascular disorders present a major public health challenge in both developed countries and countries with emerging economies. Hypertension and associated complications including stroke and myocardial infarction have reached pandemic levels. Current management strategies of hypertension predominantly include the utilization of pharmaceutical drugs which are often associated with undesirable side effects. Moreover, the drugs are often too expensive for populations from resource-limited Southern African rural, and some urban, communities. As a result, most patients rely on ethno-medicinal plants for the treatment of a variety of diseases including cardiovascular and metabolic disorders. The effectiveness of these plants in managing several cardiovascular diseases has been attributed to the presence of bioactive phytochemical constituents. In this review, the treatment options that target the renin-angiotensin system (RAS) in the management of hypertension were summarized, with special emphasis on ethno-medicinal plants and their influence on the ACE1 RAS pathway. The dearth of knowledge regarding the effect of ethno-medicinal plants on the ACE2 pathway was also highlighted.
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Affiliation(s)
- Pietro De Lange-Jacobs
- Department of Human Anatomy and Physiology, University of Johannesburg, Doornfontein Campus, Corner Beit and Siemert Streets, Doornfontein, Johannesburg 2000, South Africa; (P.D.L.-J.); (A.S.-K.); (B.T.)
| | - Asma Shaikh-Kader
- Department of Human Anatomy and Physiology, University of Johannesburg, Doornfontein Campus, Corner Beit and Siemert Streets, Doornfontein, Johannesburg 2000, South Africa; (P.D.L.-J.); (A.S.-K.); (B.T.)
| | - Bianca Thomas
- Department of Human Anatomy and Physiology, University of Johannesburg, Doornfontein Campus, Corner Beit and Siemert Streets, Doornfontein, Johannesburg 2000, South Africa; (P.D.L.-J.); (A.S.-K.); (B.T.)
| | - Trevor T. Nyakudya
- Department of Human Anatomy and Physiology, University of Johannesburg, Doornfontein Campus, Corner Beit and Siemert Streets, Doornfontein, Johannesburg 2000, South Africa; (P.D.L.-J.); (A.S.-K.); (B.T.)
- Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria 0002, South Africa
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Berger RCM, Benetti A, Girardi ACC, Forechi L, de Oliveira RM, Vassallo PF, Mill JG. Influence of Long-Term Salt Diets on Cardiac Ca2+ Handling and Contractility Proteins in Hypertensive Rats. Am J Hypertens 2018. [PMID: 29518186 DOI: 10.1093/ajh/hpy023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND High sodium intake contributes to the pathogenesis of hypertension and adversely affects cardiac function. Conversely, sodium reduction is associated with a blood pressure decrease and improved cardiovascular function. However, the mechanisms that underlie the cardiac effects induced by salt intake in hypertension have not been fully elucidated. Ca2+ handling is critical for efficient myocardial function; thus, we aimed to investigate the long-term effects of diets with different salt contents on cardiac function and Ca2+ handling proteins in spontaneously hypertensive rats (SHRs). METHODS Cardiac function was evaluated by catheterization. Ca2+ handling and contractile proteins were evaluated by immunoblotting in hearts from SHRs fed for 6 months with diets containing high (HS, 3%), low (LS, 0.03%), or normal salt content (NS, 0.3%). Diets were introduced immediately after weaning. Tail cuff pletismography was assessed at the 3rd and 7th months of follow-up. RESULTS Compared to the NS group, the HS group exhibited worsened hypertension, increased cardiac expression of β-myosin heavy chain (MHC), a decreased α/β-MHC ratio and reduced expression of both phospholamban (PLB) and Na+/Ca2+ exchanger (NCX). LS intake attenuated the blood pressure increase and left ventricle hypertrophy, slightly decreased the cardiac contractility and relaxation index, and increased the α/β-MHC ratio. These effects were accompanied by increased cardiac PLB expression and decreased Ca2+ L-type channel and NCX expression. CONCLUSIONS These findings indicate that the modulation of Ca2+ handling may be one of the molecular mechanisms underlying the effect of salt intake on myocardial function in hypertension.
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Affiliation(s)
| | - Acaris Benetti
- Heart Institute (InCor), University of São Paulo Medical School, São Paulo, São Paulo, Brazil
| | | | - Ludimila Forechi
- Department of Physiological Sciences, Federal University of Espirito Santo, Vitória, Espirito Santo, Brazil
| | | | - Paula Frizera Vassallo
- Department of Physiological Sciences, Federal University of Espirito Santo, Vitória, Espirito Santo, Brazil
| | - José Geraldo Mill
- Department of Physiological Sciences, Federal University of Espirito Santo, Vitória, Espirito Santo, Brazil
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Santos RAS, Sampaio WO, Alzamora AC, Motta-Santos D, Alenina N, Bader M, Campagnole-Santos MJ. The ACE2/Angiotensin-(1-7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1-7). Physiol Rev 2018; 98:505-553. [PMID: 29351514 PMCID: PMC7203574 DOI: 10.1152/physrev.00023.2016] [Citation(s) in RCA: 762] [Impact Index Per Article: 108.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Revised: 05/09/2017] [Accepted: 06/18/2017] [Indexed: 12/16/2022] Open
Abstract
The renin-angiotensin system (RAS) is a key player in the control of the cardiovascular system and hydroelectrolyte balance, with an influence on organs and functions throughout the body. The classical view of this system saw it as a sequence of many enzymatic steps that culminate in the production of a single biologically active metabolite, the octapeptide angiotensin (ANG) II, by the angiotensin converting enzyme (ACE). The past two decades have revealed new functions for some of the intermediate products, beyond their roles as substrates along the classical route. They may be processed in alternative ways by enzymes such as the ACE homolog ACE2. One effect is to establish a second axis through ACE2/ANG-(1-7)/MAS, whose end point is the metabolite ANG-(1-7). ACE2 and other enzymes can form ANG-(1-7) directly or indirectly from either the decapeptide ANG I or from ANG II. In many cases, this second axis appears to counteract or modulate the effects of the classical axis. ANG-(1-7) itself acts on the receptor MAS to influence a range of mechanisms in the heart, kidney, brain, and other tissues. This review highlights the current knowledge about the roles of ANG-(1-7) in physiology and disease, with particular emphasis on the brain.
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Affiliation(s)
- Robson Augusto Souza Santos
- National Institute of Science and Technology in Nanobiopharmaceutics, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais , Belo Horizonte , Brazil ; Department of Biological Sciences, Federal University of Ouro Preto , Ouro Preto , Brazil ; Max-Delbrück-Center for Molecular Medicine (MDC), Berlin , Germany ; Berlin Institute of Health (BIH), Berlin , Germany ; Charité - University Medicine, Berlin , Germany ; DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin , Germany ; Institute for Biology, University of Lübeck , Lübeck , Germany
| | - Walkyria Oliveira Sampaio
- National Institute of Science and Technology in Nanobiopharmaceutics, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais , Belo Horizonte , Brazil ; Department of Biological Sciences, Federal University of Ouro Preto , Ouro Preto , Brazil ; Max-Delbrück-Center for Molecular Medicine (MDC), Berlin , Germany ; Berlin Institute of Health (BIH), Berlin , Germany ; Charité - University Medicine, Berlin , Germany ; DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin , Germany ; Institute for Biology, University of Lübeck , Lübeck , Germany
| | - Andreia C Alzamora
- National Institute of Science and Technology in Nanobiopharmaceutics, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais , Belo Horizonte , Brazil ; Department of Biological Sciences, Federal University of Ouro Preto , Ouro Preto , Brazil ; Max-Delbrück-Center for Molecular Medicine (MDC), Berlin , Germany ; Berlin Institute of Health (BIH), Berlin , Germany ; Charité - University Medicine, Berlin , Germany ; DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin , Germany ; Institute for Biology, University of Lübeck , Lübeck , Germany
| | - Daisy Motta-Santos
- National Institute of Science and Technology in Nanobiopharmaceutics, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais , Belo Horizonte , Brazil ; Department of Biological Sciences, Federal University of Ouro Preto , Ouro Preto , Brazil ; Max-Delbrück-Center for Molecular Medicine (MDC), Berlin , Germany ; Berlin Institute of Health (BIH), Berlin , Germany ; Charité - University Medicine, Berlin , Germany ; DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin , Germany ; Institute for Biology, University of Lübeck , Lübeck , Germany
| | - Natalia Alenina
- National Institute of Science and Technology in Nanobiopharmaceutics, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais , Belo Horizonte , Brazil ; Department of Biological Sciences, Federal University of Ouro Preto , Ouro Preto , Brazil ; Max-Delbrück-Center for Molecular Medicine (MDC), Berlin , Germany ; Berlin Institute of Health (BIH), Berlin , Germany ; Charité - University Medicine, Berlin , Germany ; DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin , Germany ; Institute for Biology, University of Lübeck , Lübeck , Germany
| | - Michael Bader
- National Institute of Science and Technology in Nanobiopharmaceutics, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais , Belo Horizonte , Brazil ; Department of Biological Sciences, Federal University of Ouro Preto , Ouro Preto , Brazil ; Max-Delbrück-Center for Molecular Medicine (MDC), Berlin , Germany ; Berlin Institute of Health (BIH), Berlin , Germany ; Charité - University Medicine, Berlin , Germany ; DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin , Germany ; Institute for Biology, University of Lübeck , Lübeck , Germany
| | - Maria Jose Campagnole-Santos
- National Institute of Science and Technology in Nanobiopharmaceutics, Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais , Belo Horizonte , Brazil ; Department of Biological Sciences, Federal University of Ouro Preto , Ouro Preto , Brazil ; Max-Delbrück-Center for Molecular Medicine (MDC), Berlin , Germany ; Berlin Institute of Health (BIH), Berlin , Germany ; Charité - University Medicine, Berlin , Germany ; DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin , Germany ; Institute for Biology, University of Lübeck , Lübeck , Germany
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Ferrario CM, VonCannon J, Jiao Y, Ahmad S, Bader M, Dell'Italia LJ, Groban L, Varagic J. Cardiac angiotensin-(1-12) expression and systemic hypertension in rats expressing the human angiotensinogen gene. Am J Physiol Heart Circ Physiol 2016; 310:H995-1002. [PMID: 26873967 DOI: 10.1152/ajpheart.00833.2015] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 02/08/2016] [Indexed: 12/12/2022]
Abstract
Angiotensin-(1-12) [ANG-(1-12)] is processed into ANG II by chymase in rodent and human heart tissue. Differences in the amino acid sequence of rat and human ANG-(1-12) render the human angiotensinogen (hAGT) protein refractory to cleavage by renin. We used transgenic rats harboring the hAGT gene [TGR(hAGT)L1623] to assess the non-renin-dependent effects of increased hAGT expression on heart function and arterial pressure. Compared with Sprague-Dawley (SD) control rats (n= 11), male homozygous TGR(hAGT)L1623 (n= 9) demonstrated sustained daytime and nighttime hypertension associated with no changes in heart rate but increased heart rate lability. Increased heart weight/tibial length ratio and echocardiographic indexes of cardiac hypertrophy were associated with modest reduction of systolic function in hAGT rats. Robust human ANG-(1-12) immunofluorescence within myocytes of TGR(hAGT)L1623 rats was associated with a fourfold increase in cardiac ANG II content. Chymase enzymatic activity, using the rat or human ANG-(1-12) as a substrate, was not different in the cardiac tissue of SD and hAGT rats. Since both cardiac angiotensin-converting enzyme (ACE) and ACE2 activities were not different among the two strains, the changes in cardiac structure and function, blood pressure, and left ventricular ANG II content might be a product of an increased cardiac expression of ANG II generated through a non-renin-dependent mechanism. The data also underscore the existence in the rat of alternate enzymes capable of acting on hAGT protein. Homozygous transgenic rats expressing the hAGT gene represent a novel tool to investigate the contribution of human relevant renin-independent cardiac ANG II formation and function.
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Affiliation(s)
- Carlos M Ferrario
- Department of Surgery, Wake Forest School of Medicine, Winston Salem, North Carolina; Departments of Medicine-Nephrology and Physiology-Pharmacology, Wake Forest School of Medicine, Winston Salem, North Carolina
| | - Jessica VonCannon
- Department of Surgery, Wake Forest School of Medicine, Winston Salem, North Carolina; Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston Salem, North Carolina
| | - Yan Jiao
- Department of Surgery, Wake Forest School of Medicine, Winston Salem, North Carolina
| | - Sarfaraz Ahmad
- Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston Salem, North Carolina
| | - Michael Bader
- Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany
| | - Louis J Dell'Italia
- Division of Cardiovascular Disease, University of Alabama at Birmingham and Department of Veterans Affairs, Birmingham Veterans Affairs Medical Center, Birmingham, Alabama
| | - Leanne Groban
- Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston Salem, North Carolina; Department of Anesthesiology, Wake Forest School of Medicine, Winston Salem, North Carolina; and
| | - Jasmina Varagic
- Department of Surgery, Wake Forest School of Medicine, Winston Salem, North Carolina; Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston Salem, North Carolina; Departments of Medicine-Nephrology and Physiology-Pharmacology, Wake Forest School of Medicine, Winston Salem, North Carolina
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López-Miranda V, Soto-Montenegro ML, Uranga-Ocio JA, Vera G, Herradón E, González C, Blas C, Martínez-Villaluenga M, López-Pérez AE, Desco M, Abalo R. Effects of chronic dietary exposure to monosodium glutamate on feeding behavior, adiposity, gastrointestinal motility, and cardiovascular function in healthy adult rats. Neurogastroenterol Motil 2015; 27:1559-70. [PMID: 26303145 DOI: 10.1111/nmo.12653] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Accepted: 07/15/2015] [Indexed: 01/29/2023]
Abstract
BACKGROUND Monosodium glutamate (MSG) is a flavor-enhancer widely used as a food additive. However, its safe dietary concentration and its toxicity, including its possible implication in the recent metabolic syndrome pandemia, is still a controversial issue. Therefore, a deep knowledge of its effects upon regular dietary use is needed. Our aim was to evaluate the effects of chronic exposure to MSG on feeding behavior, abdominal fat, gastrointestinal motility, and cardiovascular function in rats. METHODS Two groups of adult male Wistar rats were used: control and treated with MSG (4 g/L in drinking water) for 6 weeks. Different functional parameters were determined and the histological structure was analyzed in tissues of interest. KEY RESULTS Compared to control animals, chronic MSG increased water intake but did not modify food ingestion or body weight gain. Neither the abdominal fat volume nor the fat fraction, measured by magnetic resonance imaging, was modified by MSG. Monosodium glutamate did not alter general gastrointestinal motility, but significantly increased the colonic response to mechanical stimulation. It slightly reduced endothelium-dependent relaxation in aorta, without significantly modifying any other cardiovascular parameters. No significant histological alterations were detected in salivary glands, intestinal wall, aorta, heart, and kidney. CONCLUSIONS & INFERENCES Chronic treatment with MSG in the adult rat increased water intake. This supports its potential to improve acceptance of low-fat regimens and to increase hydration in the elderly and sportspeople, often at risk of dehydration. Changes in colonic contractility and cardiovascular function could have some long-term repercussions warranting further research.
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Affiliation(s)
- V López-Miranda
- Área de Farmacología y Nutrición y Unidad Asociada al Instituto de Química Médica(IQM) y al Centro de Investigación de Alimentos (CIAL) del Consejo Superior de Investigaciones Científicas (CSIC), Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain
| | - M L Soto-Montenegro
- Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.,CIBER de Salud Mental (CIBERSAM), Madrid, Spain
| | - J A Uranga-Ocio
- Área de Histología y Anatomía Patológica y Unidad Asociada al Centro de Investigación de Alimentos (CIAL), Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain
| | - G Vera
- Área de Farmacología y Nutrición y Unidad Asociada al Instituto de Química Médica(IQM) y al Centro de Investigación de Alimentos (CIAL) del Consejo Superior de Investigaciones Científicas (CSIC), Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain
| | - E Herradón
- Área de Farmacología y Nutrición y Unidad Asociada al Instituto de Química Médica(IQM) y al Centro de Investigación de Alimentos (CIAL) del Consejo Superior de Investigaciones Científicas (CSIC), Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain
| | - C González
- Área de Farmacología y Nutrición y Unidad Asociada al Instituto de Química Médica(IQM) y al Centro de Investigación de Alimentos (CIAL) del Consejo Superior de Investigaciones Científicas (CSIC), Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain
| | - C Blas
- Área de Farmacología y Nutrición y Unidad Asociada al Instituto de Química Médica(IQM) y al Centro de Investigación de Alimentos (CIAL) del Consejo Superior de Investigaciones Científicas (CSIC), Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain
| | - M Martínez-Villaluenga
- Área de Farmacología y Nutrición y Unidad Asociada al Instituto de Química Médica(IQM) y al Centro de Investigación de Alimentos (CIAL) del Consejo Superior de Investigaciones Científicas (CSIC), Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain
| | - A E López-Pérez
- Unidad del Dolor, Servicio de Anestesiología, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - M Desco
- Dept. Bioingeniería e Ingeniería Aeroespacial, Universidad Carlos III de Madrid, Madrid, Spain
| | - R Abalo
- Área de Farmacología y Nutrición y Unidad Asociada al Instituto de Química Médica(IQM) y al Centro de Investigación de Alimentos (CIAL) del Consejo Superior de Investigaciones Científicas (CSIC), Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain
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Increase in Vascular Injury of Sodium Overloaded Mice May be Related to Vascular Angiotensin Modulation. PLoS One 2015; 10:e0128141. [PMID: 26030299 PMCID: PMC4451144 DOI: 10.1371/journal.pone.0128141] [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: 10/31/2014] [Accepted: 04/22/2015] [Indexed: 01/07/2023] Open
Abstract
This study aimed to analyzing the effect of chronic sodium overload upon carotid and femoral injury, and its relation to vascular angiotensin modulation. Male C57Bl6 mice were divided in: control (cont), receiving 1% NaCl solution for 2 weeks (salt-2) or 12 weeks (salt-12). Two-weeks before the end of the study, a 2mm catheter was implanted around the left femoral and carotid arteries to induce injury. Blood pressure (BP) and heart rate (HR) were measured at the end of the study by tail plethysmography. Arteries were collected and prepared for histological analysis to determine arterial thickening and perivascular collagen deposition. Angiotensin II and Ang(1-7) were quantified in fresh arteries using the HPLC method. There were no differences in body weight, BP and HR. Intima/media ratio had a similar increase in both injured arteries of cont and salt-2 mice, but a more pronounced increase was observed in salt-12 mice (31.1±6%). On the other hand, sodium overload modified perivascular collagen deposition, increasing thick fibers (cont: 0.5%; salt-2: 3.4%; salt-12: 0.6%) and decreasing thin fibers (cont: 7.4%; salt-2: 0.5%; salt-12: 6.8%) in non-injured arteries. Injured arteries presented similar collagen fiber distribution. Angiotensin quantification showed increased Ang(1-7) in salt treated mice (salt-2: +72%; salt-12: +45%) with a concomitant decrease in Ang II (salt-2: -54%; salt-12: -60%). Vascular injury increased significantly Ang(1-7) in salt-12 mice (+80%), maintaining Ang II reduction similar to that of a non-injured artery. The lack of changes in BP and HR suggests that the structural changes observed may be due to non-hemodynamic mechanisms such as local renin-angiotensin system. Collagen evaluation suggests that sodium overload induces time-related changes in vascular remodeling. The increase of artery injury with concomitant increase in Ang(1-7) in 12-week treated mice shows a direct association between the duration of salt treatment and the magnitude of vascular injury.
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Bader M, Alenina N, Andrade-Navarro MA, Santos RA. MAS and its related G protein-coupled receptors, Mrgprs. Pharmacol Rev 2014; 66:1080-105. [PMID: 25244929 DOI: 10.1124/pr.113.008136] [Citation(s) in RCA: 131] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
The Mas-related G protein-coupled receptors (Mrgprs or Mas-related genes) comprise a subfamily of receptors named after the first discovered member, Mas. For most Mrgprs, pruriception seems to be the major function based on the following observations: 1) they are relatively promiscuous in their ligand specificity with best affinities for itch-inducing substances; 2) they are expressed in sensory neurons and mast cells in the skin, the main cellular components of pruriception; and 3) they appear in evolution first in tetrapods, which have arms and legs necessary for scratching to remove parasites or other noxious substances from the skin before they create harm. Because parasites coevolved with hosts, each species faced different parasitic challenges, which may explain another striking observation, the multiple independent duplication and expansion events of Mrgpr genes in different species as a consequence of parallel adaptive evolution. Their predominant expression in dorsal root ganglia anticipates additional functions of Mrgprs in nociception. Some Mrgprs have endogenous ligands, such as β-alanine, alamandine, adenine, RF-amide peptides, or salusin-β. However, because the functions of these agonists are still elusive, the physiologic role of the respective Mrgprs needs to be clarified. The best studied Mrgpr is Mas itself. It was shown to be a receptor for angiotensin-1-7 and to exert mainly protective actions in cardiovascular and metabolic diseases. This review summarizes the current knowledge about Mrgprs, their evolution, their ligands, their possible physiologic functions, and their therapeutic potential.
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Affiliation(s)
- Michael Bader
- Max-Delbrück-Center for Molecular Medicine, Berlin, Germany (M.B., N.A., M.A.A.-N.); Charité-University Medicine, Berlin, Germany (M.B.); Institute for Biology, University of Lübeck, Lübeck, Germany (M.B.); and Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Brazil (M.B., N.A., R.A.S.)
| | - Natalia Alenina
- Max-Delbrück-Center for Molecular Medicine, Berlin, Germany (M.B., N.A., M.A.A.-N.); Charité-University Medicine, Berlin, Germany (M.B.); Institute for Biology, University of Lübeck, Lübeck, Germany (M.B.); and Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Brazil (M.B., N.A., R.A.S.)
| | - Miguel A Andrade-Navarro
- Max-Delbrück-Center for Molecular Medicine, Berlin, Germany (M.B., N.A., M.A.A.-N.); Charité-University Medicine, Berlin, Germany (M.B.); Institute for Biology, University of Lübeck, Lübeck, Germany (M.B.); and Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Brazil (M.B., N.A., R.A.S.)
| | - Robson A Santos
- Max-Delbrück-Center for Molecular Medicine, Berlin, Germany (M.B., N.A., M.A.A.-N.); Charité-University Medicine, Berlin, Germany (M.B.); Institute for Biology, University of Lübeck, Lübeck, Germany (M.B.); and Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Brazil (M.B., N.A., R.A.S.)
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9
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Patel SK, Velkoska E, Freeman M, Wai B, Lancefield TF, Burrell LM. From gene to protein-experimental and clinical studies of ACE2 in blood pressure control and arterial hypertension. Front Physiol 2014; 5:227. [PMID: 25009501 PMCID: PMC4067757 DOI: 10.3389/fphys.2014.00227] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Accepted: 06/02/2014] [Indexed: 12/13/2022] Open
Abstract
Hypertension is a major risk factor for stroke, coronary events, heart and renal failure, and the renin-angiotensin system (RAS) plays a major role in its pathogenesis. Within the RAS, angiotensin converting enzyme (ACE) converts angiotensin (Ang) I into the vasoconstrictor Ang II. An “alternate” arm of the RAS now exists in which ACE2 counterbalances the effects of the classic RAS through degradation of Ang II, and generation of the vasodilator Ang 1-7. ACE2 is highly expressed in the heart, blood vessels, and kidney. The catalytically active ectodomain of ACE2 undergoes shedding, resulting in ACE2 in the circulation. The ACE2 gene maps to a quantitative trait locus on the X chromosome in three strains of genetically hypertensive rats, suggesting that ACE2 may be a candidate gene for hypertension. It is hypothesized that disruption of tissue ACE/ACE2 balance results in changes in blood pressure, with increased ACE2 expression protecting against increased blood pressure, and ACE2 deficiency contributing to hypertension. Experimental hypertension studies have measured ACE2 in either the heart or kidney and/or plasma, and have reported that deletion or inhibition of ACE2 leads to hypertension, whilst enhancing ACE2 protects against the development of hypertension, hence increasing ACE2 may be a therapeutic option for the management of high blood pressure in man. There have been relatively few studies of ACE2, either at the gene or the circulating level in patients with hypertension. Plasma ACE2 activity is low in healthy subjects, but elevated in patients with cardiovascular risk factors or cardiovascular disease. Genetic studies have investigated ACE2 gene polymorphisms with either hypertension or blood pressure, and have produced largely inconsistent findings. This review discusses the evidence regarding ACE2 in experimental hypertension models and the association between circulating ACE2 activity and ACE2 polymorphisms with blood pressure and arterial hypertension in man.
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Affiliation(s)
- Sheila K Patel
- Department of Medicine, Austin Health, University of Melbourne Heidelberg, VIC, Australia
| | - Elena Velkoska
- Department of Medicine, Austin Health, University of Melbourne Heidelberg, VIC, Australia
| | - Melanie Freeman
- Department of Medicine, Austin Health, University of Melbourne Heidelberg, VIC, Australia
| | - Bryan Wai
- Department of Medicine, Austin Health, University of Melbourne Heidelberg, VIC, Australia ; Department of Cardiology, Austin Health, University of Melbourne Heidelberg, VIC, Australia
| | - Terase F Lancefield
- Department of Medicine, Austin Health, University of Melbourne Heidelberg, VIC, Australia
| | - Louise M Burrell
- Department of Medicine, Austin Health, University of Melbourne Heidelberg, VIC, Australia ; Department of Cardiology, Austin Health, University of Melbourne Heidelberg, VIC, Australia ; Department of Cardiology, The Northern Hospital, University of Melbourne Epping, VIC, Australia
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Angiotensin-(1-7) and angiotensin-(1-9): function in cardiac and vascular remodelling. Clin Sci (Lond) 2014; 126:815-27. [PMID: 24593683 DOI: 10.1042/cs20130436] [Citation(s) in RCA: 101] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The RAS (renin-angiotensin system) is integral to cardiovascular physiology; however, dysregulation of this system largely contributes to the pathophysiology of CVD (cardiovascular disease). It is well established that AngII (angiotensin II), the main effector of the RAS, engages the AT1R (angiotensin type 1 receptor) and promotes cell growth, proliferation, migration and oxidative stress, all processes which contribute to remodelling of the heart and vasculature, ultimately leading to the development and progression of various CVDs, including heart failure and atherosclerosis. The counter-regulatory axis of the RAS, which is centred on the actions of ACE2 (angiotensin-converting enzyme 2) and the resultant production of Ang-(1-7) [angiotensin-(1-7)] from AngII, antagonizes the actions of AngII via the receptor Mas, thereby providing a protective role in CVD. More recently, another ACE2 metabolite, Ang-(1-9) [angiotensin-(1-9)], has been reported to be a biologically active peptide within the counter-regulatory axis of the RAS. The present review will discuss the role of the counter-regulatory RAS peptides Ang-(1-7) and Ang-(1-9) in the cardiovascular system, with a focus on their effects in remodelling of the heart and vasculature.
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Nebivolol reduces cardiac angiotensin II, associated oxidative stress and fibrosis but not arterial pressure in salt-loaded spontaneously hypertensive rats. J Hypertens 2012; 30:1766-74. [PMID: 22895019 DOI: 10.1097/hjh.0b013e328356766f] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OBJECTIVES Increased sympathetic outflow, renin-angiotensin system (RAS) activity, and oxidative stress are critical mechanisms underlying the adverse cardiovascular effects of dietary salt excess. Nebivolol is a third-generation, highly selective β1-receptor blocker with RAS-reducing effects and additional antioxidant properties. This study evaluated the hypothesis that nebivolol reduces salt-induced cardiac remodeling and dysfunction in spontaneous hypertensive rats (SHRs) by suppressing cardiac RAS and oxidative stress. METHODS Male SHRs (8 weeks of age) were given an 8% high salt diet (HSD; n = 22), whereas their age-matched controls (n = 10) received standard chow. In a subgroup of HSD rats (n = 11), nebivolol was given at a dose of 10 mg/kg per day by gastric gavage. RESULTS After 5 weeks, HSD exacerbated hypertension as well as increased left-ventricular weight and collagen deposition while impairing left-ventricular relaxation. Salt-induced cardiac remodeling and dysfunction were associated with increased plasma renin concentration (PRC), cardiac angiotensin II immunostaining, and angiotensin-converting enzyme (ACE)/ACE2 mRNA and activity ratio. HSD also increased cardiac 3-nitrotyrosine staining indicating enhanced oxidative stress. Nebivolol treatment did not alter the salt-induced increase in arterial pressure, left-ventricular weight, and cardiac dysfunction but reduced PRC, cardiac angiotensin II immunostaining, ACE/ACE2 ratio, oxidative stress, and fibrosis. CONCLUSIONS Our data suggest that nebivolol, in a blood pressure-independent manner, ameliorated cardiac oxidative stress and associated fibrosis in salt-loaded SHRs. The beneficial effects of nebivolol may be attributed, at least in part, to the decreased ACE/ACE2 ratio and consequent reduction of cardiac angiotensin II levels.
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Lo J, Patel VB, Wang Z, Levasseur J, Kaufman S, Penninger JM, Oudit GY. Angiotensin-converting enzyme 2 antagonizes angiotensin II-induced pressor response and NADPH oxidase activation in Wistar-Kyoto rats and spontaneously hypertensive rats. Exp Physiol 2012; 98:109-22. [PMID: 22750422 DOI: 10.1113/expphysiol.2012.067165] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Angiotensin-converting enzyme 2 (ACE2), a monocarboxypeptidase capable of metabolizing angiotensin II (Ang II) into angiotensin-(1-7) [Ang-(1-7)], has emerged as a potential therapeutic target. We hypothesized that ACE2 is a negative regulator of Ang II-mediated pathological effects in vivo. In Wistar-Kyoto (WKY) rats, Ang II infusion (0.1 μg min(-1) kg(-1)) induced a pressor response, activation of NADPH oxidase and generation of superoxide in the heart, kidney and blood vessels; these effects were significantly blunted by recombinant human ACE2 (rhACE2; 2 mg kg(-1)), in association with a lowering of plasma Ang II and elevation of Ang-(1-7) levels. In the spontaneously hypertensive rat (SHR) model, rhACE2 (2 mg kg(-1) day(-1)) delivered over a 14 day period partly corrected the hypertension, the NADPH oxidase activation and the increased superoxide generation in the heart, kidney and blood vessels. Treatment with rhACE2 inhibited Ang II-mediated phosphorylation of the myocardial extracellular signal-regulated kinase 1/2 pathway in WKY rats, with congruent results seen in SHR hearts. Hence, rhACE2 is an important negative regulator of the Ang II-induced pressor response and NADPH oxidase activation and suppresses pathological myocardial signalling, thereby providing a novel therapeutic agent with which to antagonize an activated renin-angiotesin system.
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Affiliation(s)
- Jennifer Lo
- Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2S2
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13
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Batlle D, Wysocki J, Soler MJ, Ranganath K. Angiotensin-converting enzyme 2: enhancing the degradation of angiotensin II as a potential therapy for diabetic nephropathy. Kidney Int 2011; 81:520-8. [PMID: 22113528 DOI: 10.1038/ki.2011.381] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase that degrades angiotensin II with high efficiency leading to the formation of angiotensin-(1-7). ACE2 within the kidneys is largely localized in tubular epithelial cells and in glomerular epithelial cells. Decreased glomerular expression of this enzyme coupled with increased expression of ACE has been described in diabetic kidney disease, both in mice and humans with type 2 diabetes. Moreover, both ACE2 genetic ablation and pharmacological ACE2 inhibition have been shown to increase albuminuria and promote glomerular injury. Studies using recombinant ACE2 have shown the ability of ACE2 to rapidly metabolize Ang II in vivo and form the basis for future studies to examine the potential of ACE2 amplification in the therapy of diabetic kidney disease and cardiovascular disease.
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Affiliation(s)
- Daniel Batlle
- Division of Nephrology and Hypertension, Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
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Gao F, Han ZQ, Zhou X, Shi R, Dong Y, Jiang TM, Li YM. High Salt Intake Accelerated Cardiac Remodeling in Spontaneously Hypertensive Rats: Time Window of Left Ventricular Functional Transition and Its Relation to Salt-Loading Doses. Clin Exp Hypertens 2011; 33:492-9. [DOI: 10.3109/10641963.2010.551795] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Varagic J, Ahmad S, Brosnihan KB, Habibi J, Tilmon RD, Sowers JR, Ferrario CM. Salt-induced renal injury in spontaneously hypertensive rats: effects of nebivolol. Am J Nephrol 2010; 32:557-66. [PMID: 21042014 DOI: 10.1159/000321471] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2010] [Accepted: 09/25/2010] [Indexed: 12/19/2022]
Abstract
BACKGROUND we investigated renal effects of nebivolol, a selective β(1)-receptor blocker with additional antioxidative ability, in spontaneously hypertensive rats (SHR) where increased salt intake induces oxidative stress and worsens renal function as a result of further activation of the renin-angiotensin and sympathetic nervous systems. METHODS male SHR were given an 8% salt diet (HS; n = 22) for 5 weeks; their age-matched controls (n = 9) received standard chow. Nebivolol was given at a dose of 10 mg/kg/day for 5 weeks in 11 HS rats. RESULTS HS increased blood pressure, plasma renin concentration, urinary protein excretion, and renal nitroxidative stress while decreasing renal blood flow and angiotensin 1-7 receptor (mas) protein expression. There was no change in angiotensin II type 1 receptor expression among the experimental groups. Nebivolol did not alter the salt-induced increase in blood pressure but reduced urinary protein excretion, plasma renin concentration, and nitroxidative stress. Nebivolol also increased neuronal NOS expression while preventing the salt-induced decrease in renal blood flow and mas protein expression. CONCLUSION nebivolol prevented salt-induced kidney injury and associated proteinuria in SHR through a blood pressure-independent mechanism. Its protective effects may be related to reduction in oxidative stress, increases in neuronal NOS and restoration of angiotensin II type 1/mas receptor balance.
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Affiliation(s)
- Jasmina Varagic
- Hypertension and Vascular Research Center, Wake Forest University, Winston-Salem, NC 27157, USA.
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Ferrario CM, Ahmad S, Joyner J, Varagic J. Advances in the renin angiotensin system focus on angiotensin-converting enzyme 2 and angiotensin-(1-7). ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2010; 59:197-233. [PMID: 20933203 PMCID: PMC5863743 DOI: 10.1016/s1054-3589(10)59007-0] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The contribution of the renin angiotensin system to physiology and pathology is undergoing a rapid reconsideration of its mechanisms from emerging new concepts implicating angiotensin-converting enzyme 2 and angiotensin-(1-7) as new elements negatively influencing the vasoconstrictor, trophic, and pro-inflammatory actions of angiotensin II. This component of the system acts to oppose the vasoconstrictor and proliferative effects on angiotensin II through signaling mechanisms mediated by the mas receptor. In addition, a reduced expression of the vasodepressor axis composed by angiotensin-converting enzyme 2 and angiotensin-(1-7) may contribute to the expression of essential hypertension, the remodeling of heart and renal function associated with this disease, and even the physiology of pregnancy and the development of eclampsia.
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Affiliation(s)
- Carlos M Ferrario
- Hypertension and Vascular Disease Research Center, Wake Forest University School of Medicine, Winston Salem, North Carolina, USA
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