Angiotensin-converting enzyme 2, angiotensin-(1-7) and Mas: new players of the renin-angiotensin system
TL;DR: Recent findings related to the biological role of the ACE2/Ang-(1-7)/Mas arm in the cardiovascular and renal systems, as well as in metabolism are discussed.
Abstract: Angiotensin (Ang)-(1-7) is now recognized as a biologically active component of the renin-angiotensin system (RAS). Ang-(1-7) appears to play a central role in the RAS because it exerts a vast array of actions, many of them opposite to those attributed to the main effector peptide of the RAS, Ang II. The discovery of the Ang-converting enzyme (ACE) homolog ACE2 brought to light an important metabolic pathway responsible for Ang-(1-7) synthesis. This enzyme can form Ang-(1-7) from Ang II or less efficiently through hydrolysis of Ang I to Ang-(1-9) with subsequent Ang-(1-7) formation by ACE. In addition, it is now well established that the G protein-coupled receptor Mas is a functional binding site for Ang-(1-7). Thus, the axis formed by ACE2/Ang-(1-7)/Mas appears to represent an endogenous counterregulatory pathway within the RAS, the actions of which are in opposition to the vasoconstrictor/proliferative arm of the RAS consisting of ACE, Ang II, and AT(1) receptor. In this brief review, we will discuss recent findings related to the biological role of the ACE2/Ang-(1-7)/Mas arm in the cardiovascular and renal systems, as well as in metabolism. In addition, we will highlight the potential interactions of Ang-(1-7) and Mas with AT(1) and AT(2) receptors.
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TL;DR: GSK2586881 was well-tolerated in patients with ARDS, and the rapid modulation of RAS peptides suggests target engagement, although the study was not powered to detect changes in acute physiology or clinical outcomes.
Abstract: Renin-angiotensin system (RAS) signaling and angiotensin-converting enzyme 2 (ACE2) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). We postulated that repleting ACE2 using GSK2586881, a recombinant form of human angiotensin-converting enzyme 2 (rhACE2), could attenuate acute lung injury. We conducted a two-part phase II trial comprising an open-label intrapatient dose escalation and a randomized, double-blind, placebo-controlled phase in ten intensive care units in North America. Patients were between the ages of 18 and 80 years, had an American-European Consensus Criteria consensus diagnosis of ARDS, and had been mechanically ventilated for less than 72 h. In part A, open-label GSK2586881 was administered at doses from 0.1 mg/kg to 0.8 mg/kg to assess safety, pharmacokinetics, and pharmacodynamics. Following review of data from part A, a randomized, double-blind, placebo-controlled investigation of twice-daily doses of GSK2586881 (0.4 mg/kg) for 3 days was conducted (part B). Biomarkers, physiological assessments, and clinical endpoints were collected over the dosing period and during follow-up. Dose escalation in part A was well-tolerated without clinically significant hemodynamic changes. Part B was terminated after 39 of the planned 60 patients following a planned futility analysis. Angiotensin II levels decreased rapidly following infusion of GSK2586881, whereas angiotensin-(1–7) and angiotensin-(1–5) levels increased and remained elevated for 48 h. Surfactant protein D concentrations were increased, whereas there was a trend for a decrease in interleukin-6 concentrations in rhACE2-treated subjects compared with placebo. No significant differences were noted in ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, oxygenation index, or Sequential Organ Failure Assessment score. GSK2586881 was well-tolerated in patients with ARDS, and the rapid modulation of RAS peptides suggests target engagement, although the study was not powered to detect changes in acute physiology or clinical outcomes. ClinicalTrials.gov, NCT01597635
. Registered on 26 January 2012.
497 citations
TL;DR: Current Opinion in Nephrology and Hypertension is an indispensable journal for the busy clinician, researcher or student with condensed reviews, supplemented with References and Recommended Reading and Current World Literature.
Abstract: Each issue contains either two or three sections delivering a diverse and comprehensive coverage of all the key issues, including pathophysiology of hypertension, circulation and hemodynamics, and clinical nephrology. Current Opinion in Nephrology and Hypertension is an indispensable journal for the busy clinician, researcher or student with condensed reviews, supplemented with References and Recommended Reading and Current World Literature a thorough bibliography compiled from the top journals in the field.
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TL;DR: Four molecular axes that may be involved in SARS-CoV-2 driven inflammatory cytokine overproduction are addressed and elucidate an array of therapeutic strategies to confront the cytokine storm in order to prevent and treat COVID-19 associated acute respiratory distress syndrome.
343 citations
TL;DR: The ACE2-mediated catabolism of angiotensin II is likely to have a major role in cardiovascular protection, whereas the relevant functions and signalling mechanisms of actions induced by ang Elliotensin 1–7 have not been conclusively determined.
Abstract: The renin-angiotensin system (RAS) has pivotal roles in the regulation of normal physiology and the pathogenesis of cardiovascular disease. Angiotensin-converting enzyme (ACE) 2, and its product angiotensin 1-7, are thought to have counteracting effects against the adverse actions of other, better known and understood, members of the RAS. The physiological and pathological importance of ACE2 and angiotensin 1-7 in the cardiovascular system are not completely understood, but numerous experimental studies have indicated that these components have protective effects in the heart and blood vessels. Here, we provide an overview on the basic properties of ACE2 and angiotensin 1-7 and a summary of the evidence from experimental and clinical studies of various pathological conditions, such as hypertension, atherosclerosis, myocardial remodelling, heart failure, ischaemic stroke, and diabetes mellitus. ACE2-mediated catabolism of angiotensin II is likely to have a major role in cardiovascular protection, whereas the relevant functions and signalling mechanisms of actions induced by angiotensin 1-7 have not been conclusively determined. The ACE2-angiotensin 1-7 pathway, however, might provide a useful therapeutic target for the treatment of cardiovascular disease, especially in patients with overactive RAS.
318 citations
Cites background from "Angiotensin-converting enzyme 2, an..."
...18, [86] [87] [88] The precise angiotensin 1-7-Mas signalling mechanisms in the context of cardio vascular physiology have not, however, been firmly established....
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...18 By contrast, angiotensin 1-7 has inhibitory effects on activated mitogen-activated protein kinase (MAPK) pathways in endothelial cells, 56 smoothmuscle cells, 57,58 cardiac myocytes, 59 and renal proximal tubular cells....
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...18 The heart, brain, and kidney are major sources of angiotensin 1-7 production....
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...18, 44 Although the biological actions of angiotensin 1-7 are well described, the signalling mechanisms are still poorly understood....
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...18, 43, 44 In addition, angiotensin 1-7 is thought to have favourable effects on metabolism by lessening insulin resistance....
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TL;DR: The roles and therapeutic implications of the vasoprotective axes of the RAS in cardiovascular, hypertensive and kidney diseases are reviewed.
317 citations
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TL;DR: Losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy, and it was generally well tolerated.
Abstract: Background Diabetic nephropathy is the leading cause of end-stage renal disease. Interruption of the renin–angiotensin system slows the progression of renal disease in patients with type 1 diabetes, but similar data are not available for patients with type 2, the most common form of diabetes. We assessed the role of the angiotensin-II–receptor antagonist losartan in patients with type 2 diabetes and nephropathy. Methods A total of 1513 patients were enrolled in this randomized, double-blind study comparing losartan (50 to 100 mg once daily) with placebo, both taken in addition to conventional antihypertensive treatment (calcium-channel antagonists, diuretics, alpha-blockers, beta-blockers, and centrally acting agents), for a mean of 3.4 years. The primary outcome was the composite of a doubling of the base-line serum creatinine concentration, end-stage renal disease, or death. Secondary end points included a composite of morbidity and mortality from cardiovascular causes, proteinuria, and the rate of prog...
6,547 citations
"Angiotensin-converting enzyme 2, an..." refers methods in this paper
...Such a relationship was prompted by clinical trials (Hansson et al. 1999, Brenner et al. 2001, Yusuf et al. 2001, Dahlof et al. 2002) and experimental studies (Oliveira et al. 2002, Furuhashi et al. 2004, Lupi et al. 2006) where the overall observation was an improvement in hyperglycemia by…...
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TL;DR: Although ATP III identified CVD as the primary clinical outcome of the metabolic syndrome, most people with this syndrome have insulin resistance, which confers increased risk for type 2 diabetes, when diabetes becomes clinically apparent, CVD risk rises sharply.
Abstract: The National Cholesterol Education Program’s Adult Treatment Panel III report (ATP III)1 identified the metabolic syndrome as a multiplex risk factor for cardiovascular disease (CVD) that is deserving of more clinical attention. The cardiovascular community has responded with heightened awareness and interest. ATP III criteria for metabolic syndrome differ somewhat from those of other organizations. Consequently, the National Heart, Lung, and Blood Institute, in collaboration with the American Heart Association, convened a conference to examine scientific issues related to definition of the metabolic syndrome. The scientific evidence related to definition was reviewed and considered from several perspectives: (1) major clinical outcomes, (2) metabolic components, (3) pathogenesis, (4) clinical criteria for diagnosis, (5) risk for clinical outcomes, and (6) therapeutic interventions.
ATP III viewed CVD as the primary clinical outcome of metabolic syndrome. Most individuals who develop CVD have multiple risk factors. In 1988, Reaven2 noted that several risk factors (eg, dyslipidemia, hypertension, hyperglycemia) commonly cluster together. This clustering he called Syndrome X , and he recognized it as a multiplex risk factor for CVD. Reaven and subsequently others postulated that insulin resistance underlies Syndrome X (hence the commonly used term insulin resistance syndrome ). Other researchers use the term metabolic syndrome for this clustering of metabolic risk factors. ATP III used this alternative term. It avoids the implication that insulin resistance is the primary or only cause of associated risk factors. Although ATP III identified CVD as the primary clinical outcome of the metabolic syndrome, most people with this syndrome have insulin resistance, which confers increased risk for type 2 diabetes. When diabetes becomes clinically apparent, CVD risk rises sharply. Beyond CVD and type 2 diabetes, individuals with metabolic syndrome seemingly are susceptible to other conditions, notably polycystic ovary syndrome, fatty liver, cholesterol gallstones, asthma, sleep disturbances, and some …
6,238 citations
"Angiotensin-converting enzyme 2, an..." refers background in this paper
...Therefore, the RAS is considered a potential target for treating the metabolic syndrome, which is charac- terized by obesity, insulin resistance, hypertension, dyslipidemia, and other symptoms (Grundy et al. 2004)....
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TL;DR: Losartan prevents more cardiovascular morbidity and death than atenolol for a similar reduction in blood pressure and is better tolerated, while new-onset diabetes was less frequent with losartan.
5,380 citations
"Angiotensin-converting enzyme 2, an..." refers methods in this paper
...Such a relationship was prompted by clinical trials (Hansson et al. 1999, Brenner et al. 2001, Yusuf et al. 2001, Dahlof et al. 2002) and experimental studies (Oliveira et al. 2002, Furuhashi et al. 2004, Lupi et al. 2006) where the overall observation was an improvement in hyperglycemia by…...
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TL;DR: The organ- and cell-specific expression of ACE2 and its unique cleavage of key vasoactive peptides suggest an essential role for ACE2 in the local renin-angiotensin system of the heart and kidney.
Abstract: ACE2, the first known human homologue of angiotensin-converting enzyme (ACE), was identified from 5' sequencing of a human heart failure ventricle cDNA library. ACE2 has an apparent signal peptide, a single metalloprotease active site, and a transmembrane domain. The metalloprotease catalytic domains of ACE2 and ACE are 42% identical, and comparison of the genomic structures indicates that the two genes arose through duplication. In contrast to the more ubiquitous ACE, ACE2 transcripts are found only in heart, kidney, and testis of 23 human tissues examined. Immunohistochemistry shows ACE2 protein predominantly in the endothelium of coronary and intrarenal vessels and in renal tubular epithelium. Active ACE2 enzyme is secreted from transfected cells by cleavage N-terminal to the transmembrane domain. Recombinant ACE2 hydrolyzes the carboxy terminal leucine from angiotensin I to generate angiotensin 1-9, which is converted to smaller angiotensin peptides by ACE in vitro and by cardiomyocytes in culture. ACE2 can also cleave des-Arg bradykinin and neurotensin but not bradykinin or 15 other vasoactive and hormonal peptides tested. ACE2 is not inhibited by lisinopril or captopril. The organ- and cell-specific expression of ACE2 and its unique cleavage of key vasoactive peptides suggest an essential role for ACE2 in the local renin-angiotensin system of the heart and kidney. The full text of this article is available at http://www. circresaha.org.
2,711 citations
"Angiotensin-converting enzyme 2, an..." refers background in this paper
...The identification of the ACE homolog, ACE2, as a key Ang-(1–7)-forming enzyme unravels the existence of a distinct enzymatic pathway for the production of this peptide (Donoghue et al. 2000, Tipnis et al. 2000)....
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...monocarboxypeptidase can remove the amino acid leucine from the C-terminus of Ang I to form the biological active peptide Ang-(1-9) (Donoghue et al. 2000; Ocaranza et al. 2006), which is subsequently cleaved to generate Ang-(1-7) through ACE and neutral-endopeptidase 24....
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...The identification of the ACE homologue, ACE2, as a key Ang-(1-7)-forming enzyme unravel the existence of a distinct enzymatic pathway for the production of this peptide (Donoghue et al. 2000; Tipnis et al. 2000)....
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TL;DR: Captopril and conventional treatment did not differ in efficacy in preventing cardiovascular morbidity and mortality and the difference in stroke risk was probably due to the lower levels of blood pressure obtained initially in previously treated patients randomised to conventional therapy.
1,991 citations
"Angiotensin-converting enzyme 2, an..." refers methods in this paper
...Such a relationship was prompted by clinical trials (Hansson et al. 1999, Brenner et al. 2001, Yusuf et al. 2001, Dahlof et al. 2002) and experimental studies (Oliveira et al. 2002, Furuhashi et al. 2004, Lupi et al. 2006) where the overall observation was an improvement in hyperglycemia by…...
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