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Drugs acting on the renin-angiotensin system and SARS-CoV-2.

ABSTRACT: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing global Coronavirus 2019 (COVID-19) pandemic, resulting in thousands of deaths worldwide and representing a health challenge with few precedents in human history. Angiotensin-converting enzyme 2 (ACE-2) facilitates the access of SARS-CoV-2 to cells. Therapeutic agents acting on the renin-angiotensin system (RAS) might be able to modulate the concentration of ACE-2 and the various components of the system. Here, we discuss current pharmacological, molecular, and clinical evidence to investigate whether drugs acting on RAS with modulation of the ACE-2 concentration have added value in combating SARS-CoV-2 infection. We also highlight the possible deleterious action of the ACE/Ang-II/AT-1r axis and possible beneficial role of the ACE-2/Ang 1-7/MasR axis in acute respiratory distress syndrome (ARDS) caused by SARS-CoV-2, discussing the possibility of addressing the various RAS components with drug treatments to improve clinical outcomes.

SUBMITTER: Vitiello A

PROVIDER: S-EPMC7825840 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Drugs acting on the renin-angiotensin system and SARS-CoV-2.

Vitiello Antonio A Pelliccia Chiara C Ferrara Francesco F

Drug discovery today 20210121 4

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the ongoing global Coronavirus 2019 (COVID-19) pandemic, resulting in thousands of deaths worldwide and representing a health challenge with few precedents in human history. Angiotensin-converting enzyme 2 (ACE-2) facilitates the access of SARS-CoV-2 to cells. Therapeutic agents acting on the renin-angiotensin system (RAS) might be able to modulate the concentration of ACE-2 and the various components of the system. ...[more]

PMID: 33486116

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Project description:BackgroundAngiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are commonly used antihypertensives. Recently, these drugs have been associated with a protective effect against pancreatic cancer, but data on this putative association remain limited. Thus, the objective of this study was to determine whether the use of ACEIs and/or ARBs is associated with a decreased risk of pancreatic cancer.MethodsWe conducted a population-based cohort study, using a nested case-control analysis within the UK Clinical Practice Research Datalink population. The cohort consisted of all patients newly treated with antihypertensive drugs between 1 January 1995 and 31 December 2009, with follow-up until 31 December 2010. Cases were patients with newly diagnosed pancreatic cancer, which were matched with up to 10 controls on age, sex, calendar year of cohort entry, and duration of follow-up. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of pancreatic cancer incidence associated with ever use of ACEIs and ARBs. A secondary analysis was conducted to assess whether the incidence of pancreatic cancer varied with cumulative duration of use of these drugs.ResultsA cohort of 547 566 was assembled. During 3 040 332 person-years of follow-up, a total of 866 patients were newly diagnosed with pancreatic cancer (rate: 3/10 000 per year) and matched to 8636 controls. Overall, when compared with other antihypertensive drugs, the use of ACEIs was not associated with a decreased risk of pancreatic cancer overall (OR: 1.01, 95% CI: 0.86-1.17) or according to cumulative duration of use. The use of ARBs was not associated with a decreased risk of pancreatic cancer overall (OR: 0.93, 95% CI: 0.75-1.15), whereas a cumulative duration of use of 1-3 years was associated with a 38% decrease (OR: 0.62, 95% CI: 0.41-0.94), which returned to the null after >3 years of use (OR: 1.04, 95% CI: 0.74-1.46).ConclusionsThe use of ARBs and ACEIs was not associated with an overall decreased risk of pancreatic cancer when compared with patients using other antihypertensive drugs. Additional research is needed to determine whether ARBs may confer a short-term protective effect.

Project description:The emergence of SARS-CoV-2/human/Wuhan/X1/2019, a virus belonging to the species Severe acute respiratory syndrome-related coronavirus, and the recognition of Coronavirus Disease 2019 (COVID-19) as a pandemic have highly increased the scientific research regarding the pathogenesis of COVID-19. The Renin Angiotensin System (RAS) seems to be involved in COVID-19 natural course, since studies suggest the membrane-bound Angiotensin-converting enzyme 2 (ACE2) works as SARS-CoV-2 cellular receptor. Besides the efforts of the scientific community to understand the virus' molecular interactions with human cells, few studies summarize what has been so far discovered about SARS-CoV-2 signaling mechanisms and its interactions with RAS molecules. This review aims to discuss possible SARS-CoV-2 intracellular signaling pathways, cell entry mechanism and the possible consequences of the interaction with RAS components, including Angiotensin II (Ang II), Angiotensin-(1-7) [Ang-(1-7)], Angiotensin-converting enzyme (ACE), ACE2, Angiotensin II receptor type-1 (AT1), and Mas Receptor. We also discuss ongoing clinical trials and treatment based on RAS cascade intervention. Data were obtained independently by the two authors who carried out a search in the PubMed, Embase, LILACS, Cochrane, Scopus, SciELO and the National Institute of Health databases using Medical Subject Heading terms as "SARS-CoV-2," "COVID-19," "Renin Angiotensin System," "ACE2," "Angiotensin II," "Angiotensin-(1-7)," and "AT1 receptor." Similarly to other members of Coronaviridae family, the molecular interactions between the pathogen and the membrane-bound ACE2 are based on the cleavage of the spike glycoprotein (S) in two subunits. Following the binding of the S1 receptor-binding domain (RBD) to ACE2, transmembrane protease/serine subfamily 2 (TMPRSS2) cleaves the S2 domain to facilitate membrane fusion. It is very likely that SARS-CoV-2 cell entry results in downregulation of membrane-bound ACE2, an enzyme that converts Ang II into Ang-(1-7). This mechanism can result in lung injury and vasoconstriction. In addition, Ang II activates pro-inflammatory cascades when binding to the AT1 Receptor. On the other hand, Ang-(1-7) promotes anti-inflammatory effects through its interactions with the Mas Receptor. These molecules might be possible therapeutic targets for treating COVID-19. Thus, the understanding of SARS-CoV-2 intracellular pathways and interactions with the RAS may clarify COVID-19 physiopathology and open perspectives for new treatments and strategies.

Project description:The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), was first identified in Eastern Asia (Wuhan, China) in December 2019. The virus then spread to Europe and across all continents where it has led to higher mortality and morbidity, and was declared as a pandemic by the World Health Organization (WHO) in March 2020. Recently, different vaccines have been produced and seem to be more or less effective in protecting from COVID-19. The renin-angiotensin system (RAS), an essential enzymatic cascade involved in maintaining blood pressure and electrolyte balance, is involved in the pathogenicity of COVID-19, since the angiotensin-converting enzyme II (ACE2) acts as the cellular receptor for SARS-CoV-2 in many human tissues and organs. In fact, the viral entrance promotes a downregulation of ACE2 followed by RAS balance dysregulation and an overactivation of the angiotensin II (Ang II)-angiotensin II type I receptor (AT1R) axis, which is characterized by a strong vasoconstriction and the induction of the profibrotic, proapoptotic and proinflammatory signalizations in the lungs and other organs. This mechanism features a massive cytokine storm, hypercoagulation, an acute respiratory distress syndrome (ARDS) and subsequent multiple organ damage. While all individuals are vulnerable to SARS-CoV-2, the disease outcome and severity differ among people and countries and depend on a dual interaction between the virus and the affected host. Many studies have already pointed out the importance of host genetic polymorphisms (especially in the RAS) as well as other related factors such age, gender, lifestyle and habits and underlying pathologies or comorbidities (diabetes and cardiovascular diseases) that could render individuals at higher risk of infection and pathogenicity. In this review, we explore the correlation between all these risk factors as well as how and why they could account for severe post-COVID-19 complications.

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Drugs acting on the renin-angiotensin system and SARS-CoV-2.

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Drugs acting on the renin-angiotensin system and SARS-CoV-2.

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