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Hypertension (Dallas, Tex. : 1979) Jan 2018
Topics: Angiotensin I; Angiotensin II; Humans; Muscle, Smooth, Vascular; Peptide Fragments
PubMed: 29203630
DOI: 10.1161/HYPERTENSIONAHA.117.10406 -
Scientific Reports Nov 2022SARS-CoV-2 gains cell entry via angiotensin-converting enzyme (ACE) 2, a membrane-bound enzyme of the "alternative" (alt) renin-angiotensin system (RAS). ACE2...
SARS-CoV-2 gains cell entry via angiotensin-converting enzyme (ACE) 2, a membrane-bound enzyme of the "alternative" (alt) renin-angiotensin system (RAS). ACE2 counteracts angiotensin II by converting it to potentially protective angiotensin 1-7. Using mass spectrometry, we assessed key metabolites of the classical RAS (angiotensins I-II) and alt-RAS (angiotensins 1-7 and 1-5) pathways as well as ACE and ACE2 concentrations in 159 patients hospitalized with COVID-19, stratified by disease severity (severe, n = 76; non-severe: n = 83). Plasma renin activity (PRA-S) was calculated as the sum of RAS metabolites. We estimated ACE activity using the angiotensin II:I ratio (ACE-S) and estimated systemic alt-RAS activation using the ratio of alt-RAS axis metabolites to PRA-S (ALT-S). We applied mixed linear models to assess how PRA-S and ACE/ACE2 concentrations affected ALT-S, ACE-S, and angiotensins II and 1-7. Median angiotensin I and II levels were higher with severe versus non-severe COVID-19 (angiotensin I: 86 versus 30 pmol/L, p < 0.01; angiotensin II: 114 versus 58 pmol/L, p < 0.05), demonstrating activation of classical RAS. The difference disappeared with analysis limited to patients not taking a RAS inhibitor (angiotensin I: 40 versus 31 pmol/L, p = 0.251; angiotensin II: 76 versus 99 pmol/L, p = 0.833). ALT-S in severe COVID-19 increased with time (days 1-6: 0.12; days 11-16: 0.22) and correlated with ACE2 concentration (r = 0.831). ACE-S was lower in severe versus non-severe COVID-19 (1.6 versus 2.6; p < 0.001), but ACE concentrations were similar between groups and correlated weakly with ACE-S (r = 0.232). ACE2 and ACE-S trajectories in severe COVID-19, however, did not differ between survivors and non-survivors. Overall RAS alteration in severe COVID-19 resembled severity of disease-matched patients with influenza. In mixed linear models, renin activity most strongly predicted angiotensin II and 1-7 levels. ACE2 also predicted angiotensin 1-7 levels and ALT-S. No single factor or the combined model, however, could fully explain ACE-S. ACE2 and ACE-S trajectories in severe COVID-19 did not differ between survivors and non-survivors. In conclusion, angiotensin II was elevated in severe COVID-19 but was markedly influenced by RAS inhibitors and driven by overall RAS activation. ACE-S was significantly lower with severe COVID-19 and did not correlate with ACE concentrations. A shift to the alt-RAS axis because of increased ACE2 could partially explain the relative reduction in angiotensin II levels.
Topics: Humans; Angiotensin-Converting Enzyme 2; Renin-Angiotensin System; Angiotensin I; COVID-19; Angiotensin II; SARS-CoV-2; Renin; Peptide Hormones; Antihypertensive Agents
PubMed: 36418458
DOI: 10.1038/s41598-022-24628-1 -
Anesthesiology Feb 2017Inhibition of Angiotensin Conversion in Experimental Renovascular Hypertension. By Miller ED Jr, Samuels A, Haber E, and Barger AC. Science 1972; 177:1108-9. Reprinted...
Inhibition of Angiotensin Conversion in Experimental Renovascular Hypertension. By Miller ED Jr, Samuels A, Haber E, and Barger AC. Science 1972; 177:1108-9. Reprinted with permission from AAAS.Constriction of the renal artery and controlled reduction of renal perfusion pressure is followed by a prompt increase in systemic renin activity and a concomitant rise in blood pressure in trained, unanesthetized dogs. The elevated blood pressure induced by the renal artery stenosis can be prevented by prior treatment with the nonapeptide Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro, which blocks conversion of angiotensin I to angiotensin II. Further, the nonapeptide can restore systemic pressure to normal in the early phase of renovascular hypertension. These results offer strong evidence that the renin- angiotensin system is responsible for the initiation of hypertension in the unilaterally nephrectomized dog with renal artery constriction.
Topics: Angiotensins; Animals; Disease Models, Animal; Dogs; History, 20th Century; Hypertension; Renal Artery Obstruction
PubMed: 27861171
DOI: 10.1097/ALN.0000000000001441 -
JAMA Apr 2023Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II...
Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor-Biased Ligand in Adults With COVID-19: Two Randomized Clinical Trials.
IMPORTANCE
Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II compared with angiotensin (1-7) and may be an important contributor to COVID-19 pathophysiology.
OBJECTIVE
To evaluate the efficacy and safety of RAS modulation using 2 investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor-biased ligand), that are hypothesized to potentiate the action of angiotensin (1-7) and mitigate the action of the angiotensin II.
DESIGN, SETTING, AND PARTICIPANTS
Two randomized clinical trials including adults hospitalized with acute COVID-19 and new-onset hypoxemia were conducted at 35 sites in the US between July 22, 2021, and April 20, 2022; last follow-up visit: July 26, 2022.
INTERVENTIONS
A 0.5-mg/kg intravenous infusion of TXA-127 once daily for 5 days or placebo. A 12-mg/h continuous intravenous infusion of TRV-027 for 5 days or placebo.
MAIN OUTCOMES AND MEASURES
The primary outcome was oxygen-free days, an ordinal outcome that classifies a patient's status at day 28 based on mortality and duration of supplemental oxygen use; an adjusted odds ratio (OR) greater than 1.0 indicated superiority of the RAS agent vs placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included allergic reaction, new kidney replacement therapy, and hypotension.
RESULTS
Both trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, and 274 [79.9%] not Hispanic), 170 received TXA-127 and 173 received placebo. Of 290 patients in the TRV-027 trial (199 [68.6%] aged 31-64 years, 168 [57.9%] men, 195 [67.2%] White, and 225 [77.6%] not Hispanic), 145 received TRV-027 and 145 received placebo. Compared with placebo, both TXA-127 (unadjusted mean difference, -2.3 [95% CrI, -4.8 to 0.2]; adjusted OR, 0.88 [95% CrI, 0.59 to 1.30]) and TRV-027 (unadjusted mean difference, -2.4 [95% CrI, -5.1 to 0.3]; adjusted OR, 0.74 [95% CrI, 0.48 to 1.13]) resulted in no difference in oxygen-free days. In the TXA-127 trial, 28-day all-cause mortality occurred in 22 of 163 patients (13.5%) in the TXA-127 group vs 22 of 166 patients (13.3%) in the placebo group (adjusted OR, 0.83 [95% CrI, 0.41 to 1.66]). In the TRV-027 trial, 28-day all-cause mortality occurred in 29 of 141 patients (20.6%) in the TRV-027 group vs 18 of 140 patients (12.9%) in the placebo group (adjusted OR, 1.52 [95% CrI, 0.75 to 3.08]). The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo.
CONCLUSIONS AND RELEVANCE
In adults with severe COVID-19, RAS modulation (TXA-127 or TRV-027) did not improve oxygen-free days vs placebo. These results do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for patients with severe COVID-19.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04924660.
Topics: Adult; Female; Humans; Male; Middle Aged; Angiotensin II; Angiotensins; COVID-19; Hypoxia; Infusions, Intravenous; Ligands; Oligopeptides; Randomized Controlled Trials as Topic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; SARS-CoV-2; Vasodilator Agents
PubMed: 37039791
DOI: 10.1001/jama.2023.3546 -
Matrix Biology : Journal of the... Sep 2020Fibrosis is characterized by excessive deposition of extracellular matrix components such as collagen in tissues or organs. Fibrosis can develop in the heart, kidneys,... (Review)
Review
Fibrosis is characterized by excessive deposition of extracellular matrix components such as collagen in tissues or organs. Fibrosis can develop in the heart, kidneys, liver, skin or any other body organ in response to injury or maladaptive reparative processes, reducing overall function and leading eventually to organ failure. A variety of cellular and molecular signaling mechanisms are involved in the pathogenesis of fibrosis. The renin-angiotensin-aldosterone system (RAAS) interacts with the potent Transforming Growth Factor β (TGFβ) pro-fibrotic pathway to mediate fibrosis in many cell and tissue types. RAAS consists of both classical and alternative pathways, which act to potentiate or antagonize fibrotic signaling mechanisms, respectively. This review provides an overview of recent literature describing the roles of RAAS in the pathogenesis of fibrosis, particularly in the liver, heart, kidney and skin, and with a focus on RAAS interactions with TGFβ signaling. Targeting RAAS to combat fibrosis represents a promising therapeutic approach, particularly given the lack of strategies for treating fibrosis as its own entity, thus animal and clinical studies to examine the impact of natural and synthetic substances to alter RAAS signaling as a means to treat fibrosis are reviewed as well.
Topics: Amides; Angiotensins; Animals; Benzimidazoles; Biphenyl Compounds; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Fumarates; Gene Expression Regulation; Humans; Kidney; Liver; Molecular Targeted Therapy; Myocardium; Pyridones; Renin-Angiotensin System; Signal Transduction; Skin; Tetrazoles; Transforming Growth Factor beta
PubMed: 32422329
DOI: 10.1016/j.matbio.2020.04.005 -
American Journal of Physiology. Renal... May 2022
Topics: Angiotensins; Kidney; Nephrectomy
PubMed: 35343851
DOI: 10.1152/ajprenal.00063.2022 -
Journal of Hypertension Aug 2021
Topics: Aldosterone; Angiotensin-Converting Enzyme 2; Angiotensins; Humans; Renin; Renin-Angiotensin System
PubMed: 34188000
DOI: 10.1097/HJH.0000000000002858 -
Synergistic actions between angiotensin-converting enzyme inhibitors and statins in atherosclerosis.Nutrition, Metabolism, and... Apr 2022Hypertension and hypercholesterolemia are independent risk factors for atherosclerotic cardiovascular disease (ASCVD) by acting directly on the endothelium and... (Review)
Review
AIMS
Hypertension and hypercholesterolemia are independent risk factors for atherosclerotic cardiovascular disease (ASCVD) by acting directly on the endothelium and activating the renin-angiotensin aldosterone system (RAAS) and mevalonate pathways. This review examines how the severity and duration of these risk factors may influence the cardiovascular risk through a reciprocal interplay leading to oxidative stress and pro-inflammatory response.
DATA SYNTHESIS
The review highlights the clinical evidence supporting the benefits of statins and angiotensin-converting enzyme (ACE) inhibitors for hypertension, lipid disorders and ASCVD management, both individually and combined, at all stages of the cardiovascular continuum.
CONCLUSION
Drug strategies incorporating an ACE-inhibitor and a statin, and in particular perindopril and atorvastatin, have consistently demonstrated reductions in the rate of ASCVD events in patients with hypertension and lipid disorders, cementing their position as first-line therapies for the management of atherosclerosis complications.
Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Atherosclerosis; Atorvastatin; Cardiovascular Diseases; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Renin-Angiotensin System
PubMed: 35082055
DOI: 10.1016/j.numecd.2021.11.015 -
Chemical Communications (Cambridge,... Dec 2022Fibrosis has been shown to develop in individuals with underlying health conditions, especially chronic inflammatory diseases. Fibrosis is often diagnosed in various... (Review)
Review
Fibrosis has been shown to develop in individuals with underlying health conditions, especially chronic inflammatory diseases. Fibrosis is often diagnosed in various organs, including the liver, lungs, kidneys, heart, and skin, and has been described as excessive accumulation of extracellular matrix that can affect specific organs in the body or systemically throughout the body. Fibrosis as a chronic condition can result in organ failure and result in death of the individual. Understanding and identification of specific biomarkers associated with fibrosis has emerging potential in the development of diagnosis and targeting treatment modalities. Therefore, in this review, we will discuss multiple signaling pathways such as TGF-β, collagen, angiotensin, and cadherin and outline the chemical nature of the different signaling pathways involved in fibrogenesis as well as the mechanisms. Although it has been well established that TGF-β is the main catalyst initiating and driving multiple pathways for fibrosis, targeting TGF-β can be challenging as this molecule regulates essential functions throughout the body that help to keep the body in homeostasis. We also discuss collagen, angiotensin, and cadherins and their role in fibrosis. We comprehensively discuss the various delivery systems used to target collagen, angiotensin, and cadherins to manage fibrosis. Nevertheless, understanding the steps by which this molecule drives fibrosis development can aid in the development of specific targets of its cascading mechanism. Throughout the review, we will demonstrate the mechanism of fibrosis targeting to improve targeting delivery and therapy.
Topics: Humans; Fibrosis; Transforming Growth Factor beta; Angiotensins; Collagen
PubMed: 36445310
DOI: 10.1039/d2cc04825f -
Pharmacological Reviews Oct 2022Discovered more than 30 years ago, the angiotensin AT receptor (ATR) has evolved from a binding site with unknown function to a firmly established major effector within... (Review)
Review
Discovered more than 30 years ago, the angiotensin AT receptor (ATR) has evolved from a binding site with unknown function to a firmly established major effector within the protective arm of the renin-angiotensin system (RAS) and a target for new drugs in development. The ATR represents an endogenous protective mechanism that can be manipulated in the majority of preclinical models to alleviate lung, renal, cardiovascular, metabolic, cutaneous, and neural diseases as well as cancer. This article is a comprehensive review summarizing our current knowledge of the ATR, from its discovery to its position within the RAS and its overall functions. This is followed by an in-depth look at the characteristics of the ATR, including its structure, intracellular signaling, homo- and heterodimerization, and expression. ATR-selective ligands, from endogenous peptides to synthetic peptides and nonpeptide molecules that are used as research tools, are discussed. Finally, we summarize the known physiological roles of the ATR and its abundant protective effects in multiple experimental disease models and expound on ATR ligands that are undergoing development for clinical use. The present review highlights the controversial aspects and gaps in our knowledge of this receptor and illuminates future perspectives for ATR research. SIGNIFICANCE STATEMENT: The angiotensin AT receptor (ATR) is now regarded as a fully functional and important component of the renin-angiotensin system, with the potential of exerting protective actions in a variety of diseases. This review provides an in-depth view of the ATR, which has progressed from being an enigma to becoming a therapeutic target.
Topics: Angiotensins; Binding Sites; Humans; Ligands; Peptides; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System
PubMed: 36180112
DOI: 10.1124/pharmrev.120.000281