Response to recent commentaries regarding the involvement of a
            ngiotensin‐converting
            enzyme 2 (
            ACE2
            ) and
            renin‐angiotensin
            system blockers in
            SARS‐CoV
            ‐2 infections

During the spread of the severe acute respiratory syndrome coronavirus-2, some reports of data still emerging and in need of full analysis indicate that certain groups of patients are at risk of COVID-19. This includes patients with hypertension, heart disease, diabetes mellitus, and clearly the elderly. Many of those patients are treated with renin-angiotensin system blockers. Because the ACE2 (angiotensin-converting enzyme 2) protein is the receptor that facilitates coronavirus entry into cells, the notion has been popularized that treatment with renin-angiotensin system blockers might increase the risk of developing a severe and fatal severe acute respiratory syndrome coronavirus-2 infection. The present article discusses this concept. ACE2 in its full-length form is a membrane-bound enzyme, whereas its shorter (soluble) form circulates in blood at very low levels. As a mono-carboxypeptidase, ACE2 contributes to the degradation of several substrates including angiotensins I and II. ACE (angiotensin-converting enzyme) inhibitors do not inhibit ACE2 because ACE and ACE2 are different enzymes. Although angiotensin II type 1 receptor blockers have been shown to upregulate ACE2 in experimental animals, the evidence is not always consistent and differs among the diverse angiotensin II type 1 receptor blockers and differing organs. Moreover, there are no data to support the notion that ACE inhibitor or angiotensin II type 1 receptor blocker administration facilitates coronavirus entry by increasing ACE2 expression in either animals or humans. Indeed, animal data support elevated ACE2 expression as conferring potential protective pulmonary and cardiovascular effects. In summary, based on the currently available evidence, treatment with renin-angiotensin system blockers should not be discontinued because of concerns with coronavirus infection.

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Renin–angiotensin system blockers, risk of SARS-CoV-2 infection and outcomes from CoViD-19: systematic review and meta-analysis

European Heart Journal - Cardiovascular Pharmacotherapy ◽

10.1093/ehjcvp/pvaa138 ◽

2020 ◽

Author(s):

Matthew M Y Lee ◽

Kieran F Docherty ◽

Naveed Sattar ◽

Neil Mehta ◽

Ankur Kalra ◽

...

Keyword(s):

Angiotensin Converting Enzyme ◽

Ace Inhibitor ◽

Meta Analysis ◽

Intensive Therapy ◽

Case Fatality ◽

Renin Angiotensin System ◽

Converting Enzyme ◽

Angiotensin System ◽

Renin Angiotensin ◽

Renin Angiotensin System Blockers

Abstract Aims This meta-analysis provides summary odds ratio (OR) estimates for associations between treatment with (vs. without) renin–angiotensin system blockers and risk of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection and coronavirus disease 2019 (CoViD-19) severity (including case-fatality) in patients with hypertension, and in all patients (irrespective of hypertension). Methods and results PubMed, EMBASE, Web of Science, Google Scholar, medRxiv, and SSRN were searched (2 May 2020 to 12 August 2020) for non-randomized observational CoViD-19 studies. Event/patient numbers were extracted, comparing angiotensin-converting enzyme (ACE) inhibitor/angiotensin-receptor blocker (ARB) treatment (and each separately), to treatment with neither drug, for the outcomes: (i) likelihood of SARS-CoV-2 infection; (ii) CoViD-19 severity [including hospitalization, intensive therapy unit (ITU), ventilation]; (iii) case-fatality. The risk of bias was assessed (ROBINS-I). Random-effects meta-analysis estimates were pooled. Eighty-six studies including 459 755 patients (103 317 with hypertension), were analysed. In patients with hypertension, ACE inhibitor or ARB treatment was not associated with a greater likelihood of SARS-CoV-2 infection in 60 141 patients (OR 1.06, 95% CI 0.99–1.14), hospitalization in 5925 patients (OR 0.90, 0.62–1.31), ITU in 7218 patients (OR 1.06, 0.73–1.56), ventilation (or ITU/ventilation/death) in 13 163 patients (OR 0.91, 0.72–1.15) or case-fatality in 18 735 patients with 2893 deaths (OR 0.75, 0.61–0.92). Conclusion Angiotensin-converting enzyme inhibitors and ARBs appear safe in the context of SARS-CoV-2 infection and should not be discontinued. PROSPERO registration number CRD42020186996.

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HYPERTENSION AND RENIN-ANGIOTENSIN SYSTEM BLOCKERS ARE NOT ASSOCIATED WITH EXPRESSION OF ANGIOTENSIN CONVERTING ENZYME 2 (ACE2) IN THE KIDNEY

Journal of Hypertension ◽

10.1097/01.hjh.0000744740.07122.70 ◽

2021 ◽

Vol 39 (Supplement 1) ◽

pp. e36-e37

Author(s):

Xiao Jiang ◽

James Eales ◽

David Scannali ◽

Alicja Nazgiewicz ◽

Priscilla Prestes ◽

...

Keyword(s):

Angiotensin Converting Enzyme ◽

Renin Angiotensin System ◽

Converting Enzyme ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Renin Angiotensin ◽

Renin Angiotensin System Blockers

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A Systematic Review and Meta-Analysis of the Use of Renin-Angiotensin System Blockers and COVID-19 Outcomes: What is the Evidence so Far and the Implications?

SSRN Electronic Journal ◽

10.2139/ssrn.3668362 ◽

2020 ◽

Author(s):

Amanj Kurdi ◽

Nouf Abutheraa ◽

Lina Akil ◽

Brian Godman

Keyword(s):

Systematic Review ◽

Meta Analysis ◽

Renin Angiotensin System ◽

Angiotensin System ◽

Renin Angiotensin ◽

Renin Angiotensin System Blockers

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Relation Between Renin-Angiotensin System Blockers and Survival Following Isolated Aortic Valve Replacement for Aortic Stenosis

The American Journal of Cardiology ◽

10.1016/j.amjcard.2017.11.013 ◽

2018 ◽

Vol 121 (4) ◽

pp. 455-460 ◽

Cited By ~ 9

Author(s):

Julien Magne ◽

Barthélémy Guinot ◽

Alexandre Le Guyader ◽

Emmanuelle Bégot ◽

Jean-Philippe Marsaud ◽

...

Keyword(s):

Aortic Valve ◽

Aortic Stenosis ◽

Aortic Valve Replacement ◽

Valve Replacement ◽

Renin Angiotensin System ◽

Angiotensin System ◽

Renin Angiotensin ◽

Renin Angiotensin System Blockers

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Pathological Role of Angiotensin II in Severe COVID-19

TH Open ◽

10.1055/s-0040-1713678 ◽

2020 ◽

Vol 04 (02) ◽

pp. e138-e144 ◽

Cited By ~ 5

Author(s):

Wolfgang Miesbach

Keyword(s):

Angiotensin Ii ◽

Angiotensin Converting Enzyme ◽

Treatment Options ◽

Renin Angiotensin System ◽

Target Cells ◽

Converting Enzyme ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Renin Angiotensin ◽

Novel Coronavirus

AbstractThe activated renin–angiotensin system induces a prothrombotic state resulting from the imbalance between coagulation and fibrinolysis. Angiotensin II is the central effector molecule of the activated renin–angiotensin system and is degraded by the angiotensin-converting enzyme 2 to angiotensin (1–7). The novel coronavirus infection (classified as COVID-19) is caused by the new coronavirus SARS-CoV-2 and is characterized by an exaggerated inflammatory response that can lead to severe manifestations such as acute respiratory distress syndrome, sepsis, and death in a proportion of patients, mostly elderly patients with preexisting comorbidities. SARS-CoV-2 uses the angiotensin-converting enzyme 2 receptor to enter the target cells, resulting in activation of the renin–angiotensin system. After downregulating the angiotensin-converting enzyme 2, the vasoconstrictor angiotensin II is increasingly produced and its counterregulating molecules angiotensin (1–7) reduced. Angiotensin II increases thrombin formation and impairs fibrinolysis. Elevated levels were strongly associated with viral load and lung injury in patients with severe COVID-19. Therefore, the complex clinical picture of patients with severe complications of COVID-19 is triggered by the various effects of highly expressed angiotensin II on vasculopathy, coagulopathy, and inflammation. Future treatment options should focus on blocking the thrombogenic and inflammatory properties of angiotensin II in COVID-19 patients.

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Resveratrol ameliorates the cyclosporine-induced vascular and renal impairments: possible impact of the modulation of renin–angiotensin system

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2018-0753 ◽

2019 ◽

Vol 97 (12) ◽

pp. 1115-1123 ◽

Cited By ~ 2

Author(s):

Seldag Bekpinar ◽

Ece Karaca ◽

Selin Yamakoğlu ◽

F. İlkay Alp-Yıldırım ◽

Vakur Olgac ◽

...

Keyword(s):

Angiotensin Ii ◽

Angiotensin Converting Enzyme ◽

Renin Angiotensin System ◽

Immunosuppressive Drug ◽

Oxidative Stress Marker ◽

Converting Enzyme ◽

Angiotensin System ◽

Renin Angiotensin ◽

System Components ◽

Renal Tubular

Cyclosporine, an immunosuppressive drug, exhibits a toxic effect on renal and vascular systems. The present study investigated whether resveratrol treatment alleviates renal and vascular injury induced by cyclosporine. Cyclosporine (25 mg/kg per day, s.c.) was given for 7 days to rats either alone or in combination with resveratrol (10 mg/kg per day, i.p.). Relaxation and contraction responses of aorta were examined. Serum levels of blood urea nitrogen, creatinine, angiotensin II, and angiotensin 1-7 were measured. Histopathological examinations as well as immunostaining for 4-hydroxynonenal and nitrotyrosine were performed in the kidney. RNA expressions of renin–angiotensin system components were also measured in renal and aortic tissues. Cyclosporine decreased the endothelium-dependent relaxation and increased vascular contraction in the aorta. It caused renal tubular degeneration and increased immunostaining for 4-hydroxynonenal, an oxidative stress marker. Cyclosporine also caused upregulations of the vasoconstrictive renin–angiotensin system components in renal (angiotensin-converting enzyme) and aortic (angiotensin II type 1 receptor) tissues. Resveratrol co-treatment prevented the cyclosporine-related deteriorations. Moreover, it induced the expressions of vasodilatory effective angiotensin-converting enzyme 2 and angiotensin II type 2 receptor in aorta and kidney, respectively. We conclude that resveratrol may be effective in preventing cyclosporine-induced renal tubular degeneration and vascular dysfunction at least in part by modulating the renin–angiotensin system.

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Anti-Hypertensive Effect of Water Extract of Danshen on Renovascular Hypertension Through Inhibition of the Renin Angiotensin System

The American Journal of Chinese Medicine ◽

10.1142/s0192415x02000107 ◽

2002 ◽

Vol 30 (01) ◽

pp. 87-93 ◽

Cited By ~ 61

Author(s):

Dae Gill Kang ◽

Yong Gab Yun ◽

Jang Hyun Ryoo ◽

Ho Sub Lee

Keyword(s):

Plasma Concentration ◽

Water Extract ◽

Renin Angiotensin System ◽

Plasma Renin ◽

Dependent Manner ◽

Converting Enzyme ◽

Angiotensin System ◽

Renin Angiotensin ◽

Ace Activity ◽

Dose Dependent

A study was designed to elucidate the mechanism of anti-hypertensive effects of Danshen in the two-kidney, one clip (2K1C) Goldblatt renovascular hypertensive model, which is the renin-angiotensin system (RAS)-dependent hypertensive model. We investigated the effects of water extracts of Danshen on the angiotensin converting enzyme (ACE) activities, systolic blood pressure (SBP), and hormone levels in the plasma of 2K1C rats. ACE activity was inhibited by the addition of Danshen extract in a dose-dependent manner. SBP was decreased significantly after administration of Danshen extract in 2K1C, whereas plasma renin activity (PRA) was not changed. The plasma concentration of aldosterone (PAC) was decreased significantly in 2K1C group administered with Danshen extract, whereas the plasma concentration of ANP was increased by administration of Danshen extract for three weeks. These results suggest that Danshen has an anti-hypertensive effect through the inhibition of ACE, an essential regulatory enzyme of RAS.

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