Modeling the Molecular Impact of SARS-CoV-2 Infection on the Renin-Angiotensin System

SARS-CoV-2 infection is mediated by the binding of its spike protein to the angiotensin-converting enzyme 2 (ACE2), which plays a pivotal role in the renin-angiotensin system (RAS). The study of RAS dysregulation due to SARS-CoV-2 infection is fundamentally important for a better understanding of the pathogenic mechanisms and risk factors associated with COVID-19 coronavirus disease and to design effective therapeutic strategies. In this context, we developed a mathematical model of RAS based on data regarding protein and peptide concentrations; the model was tested on clinical data from healthy normotensive and hypertensive individuals. We used our model to analyze the impact of SARS-CoV-2 infection on RAS, which we modeled through a downregulation of ACE2 as a function of viral load. We also used it to predict the effect of RAS-targeting drugs, such as RAS-blockers, human recombinant ACE2, and angiotensin 1–7 peptide, on COVID-19 patients; the model predicted an improvement of the clinical outcome for some drugs and a worsening for others. Our model and its predictions constitute a valuable framework for in silico testing of hypotheses about the COVID-19 pathogenic mechanisms and the effect of drugs aiming to restore RAS functionality.

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Outcomes of COVID-19 Hospitalized Patients Previously Treated with Renin-Angiotensin System Inhibitors

Journal of Clinical Medicine ◽

10.3390/jcm9113472 ◽

2020 ◽

Vol 9 (11) ◽

pp. 3472 ◽

Cited By ~ 1

Author(s):

Elena-Mihaela Cordeanu ◽

Lucas Jambert ◽

Francois Severac ◽

Hélène Lambach ◽

Jonathan Tousch ◽

...

Keyword(s):

Renin Angiotensin System ◽

Severe Pneumonia ◽

University Hospital ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Renin Angiotensin ◽

Previously Treated ◽

The Impact ◽

Harmful Effects ◽

Observation Period

(1) Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) penetrates respiratory epithelium through angiotensin-converting enzyme-2 binding, raising concerns about the potentially harmful effects of renin–angiotensin system inhibitors (RASi) on Human Coronavirus Disease 2019 (COVID-19) evolution. This study aimed to provide insight into the impact of RASi on SARS-CoV-2 outcomes in patients hospitalized for COVID-19. (2) Methods: This was a retrospective analysis of hospitalized adult patients with SARS-CoV-2 infection admitted to a university hospital in France. The observation period ended at hospital discharge. (3) Results: During the study period, 943 COVID-19 patients were admitted to our institution, of whom 772 were included in this analysis. Among them, 431 (55.8%) had previously known hypertension. The median age was 68 (56–79) years. Overall, 220 (28.5%) patients were placed under mechanical ventilation and 173 (22.4%) died. According to previous exposure to RASi, we defined two groups, namely, “RASi” (n = 282) and “RASi-free” (n = 490). Severe pneumonia (defined as leading to death and/or requiring intubation, high-flow nasal oxygen, noninvasive ventilation, and/or oxygen flow at a rate of ≥5 L/min) and death occurred more frequently in RASi-treated patients (64% versus 53% and 29% versus 19%, respectively). However, in a propensity score-matched cohort derived from the overall population, neither death (hazard ratio (HR) 0.93 (95% confidence interval (CI) 0.57–1.50), p = 0.76) nor severe pneumonia (HR 1.03 (95%CI 0.73–1.44), p = 0.85) were associated with RASi therapy. (4) Conclusion: Our study showed no correlation between previous RASi treatment and death or severe COVID-19 pneumonia after adjustment for confounders.

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SARS-CoV-2 – the Hidden Agonist of the Pressor Arm Within the Renin-Angiotensin System: Considerations for Statins and Propionate Derivatives

Journal of Medical and Radiation Oncology ◽

10.53011/jmro.2021.01.12 ◽

2021 ◽

Vol 1 (1) ◽

pp. 131-138

Author(s):

Cosmin Andrei Cismaru ◽

Gabriel Laurențiu Cismaru ◽

Claudia Cristina Burz ◽

Andreea Nutu ◽

Ioana Berindan Neagoe

Keyword(s):

Cardiovascular Disease ◽

Severe Acute Respiratory Syndrome ◽

Renin Angiotensin System ◽

Converting Enzyme ◽

Physiological Mechanisms ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Renin Angiotensin ◽

Ras Blockers

"Coronavirus disease 2019 (COVID-19) has become a serious healthcare problem, causing more than 2 million fatalities worldwide. Several treatments used for the management of chronic diseases such as hypertension, cardiovascular disease, diabetes and arthritis were shown to increase the expression of the receptor exploited by the virus, the angiotensin-converting enzyme 2 (ACE2), in vitro. This raises concerns on the safety of continuing such drugs or switching to other classes that don’t interfere with the receptor exploited by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we emphasize the mechanisms behind the regulation of ACE2 expression by several widely used drugs with possible interactions with COVID-19. Moreover, we discuss how the physiological mechanisms of attenuating inflammation and fibrosis can lead to increased expression of the receptor exploited by the virus and how this expression is further influenced be statins, propionate derivative nonsteroidal antiinflamatory drugs (NSAIDs) and renin-angiotensin system (RAS) blockers."

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Interactions between ibuprofen, ACE2, renin‐angiotensin system, and spike protein in the lung. Implications for COVID‐19

Clinical and Translational Medicine ◽

10.1002/ctm2.371 ◽

2021 ◽

Vol 11 (4) ◽

Author(s):

Rita Valenzuela ◽

Maria A. Pedrosa ◽

Pablo Garrido‐Gil ◽

Carmen M. Labandeira ◽

Gemma Navarro ◽

...

Keyword(s):

Renin Angiotensin System ◽

Spike Protein ◽

Angiotensin System ◽

Renin Angiotensin

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Incidence and factors associated with prescribing renin‐angiotensin‐system inhibitors in adult idiopathic nephrotic syndrome: A nationwide cohort study

Journal of Clinical Hypertension ◽

10.1111/jch.14224 ◽

2021 ◽

Author(s):

Hiroki Nishiwaki ◽

Kakuya Niihata ◽

Sayaka Shimizu ◽

Yugo Shibagaki ◽

Ryohei Yamamoto ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Cohort Study ◽

Idiopathic Nephrotic Syndrome ◽

Renin Angiotensin System ◽

Angiotensin System ◽

Renin Angiotensin ◽

Factors Associated

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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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Effects of Yinchenhao decoction on self-regulation of renin-angiotensin system by targeting angiotensin converting enzyme 2 in bile duct-ligated rat liver

Journal of Huazhong University of Science and Technology [Medical Sciences] ◽

10.1007/s11596-015-1463-9 ◽

2015 ◽

Vol 35 (4) ◽

pp. 519-524 ◽

Cited By ~ 4

Author(s):

Lin Wu ◽

Pi-qi Zhou ◽

Ji-wen Xie ◽

Rui Zhu ◽

Sun-chang Zhou ◽

...

Keyword(s):

Bile Duct ◽

Angiotensin Converting Enzyme ◽

Rat Liver ◽

Self Regulation ◽

Renin Angiotensin System ◽

Converting Enzyme ◽

Angiotensin System ◽

Angiotensin Converting Enzyme 2 ◽

Renin Angiotensin

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Gene variants of the renin–angiotensin system and hypertension: from a trough of disillusionment to a welcome phase of enlightenment?

Clinical Science ◽

10.1042/cs20090498 ◽

2010 ◽

Vol 118 (8) ◽

pp. 487-506 ◽

Cited By ~ 10

Author(s):

Gavin R. Norton ◽

Richard Brooksbank ◽

Angela J. Woodiwiss

Keyword(s):

Association Studies ◽

Large Population ◽

Renin Angiotensin System ◽

Human Populations ◽

Incomplete Penetrance ◽

Gene Variants ◽

Angiotensin System ◽

Renin Angiotensin ◽

Ras Genes ◽

The Impact

There is substantial evidence to suggest that BP (blood pressure) is an inherited trait. The introduction of gene technologies in the late 1980s generated a sharp phase of over-inflated prospects for polygenic traits such as hypertension. Not unexpectedly, the identification of the responsible loci in human populations has nevertheless proved to be a considerable challenge. Common variants of the RAS (renin–angiotensin system) genes, including of ACE (angiotensin-converting enzyme) and AGT (angiotensinogen) were some of the first shown to be associated with BP. Presently, ACE and AGT are the only gene variants with functional relevance, where linkage studies showing relationships with hypertension have been reproduced in some studies and where large population-based and prospective studies have demonstrated these genes to be predictors of hypertension or BP. Nevertheless, a lack of reproducibility in other linkage and association studies has generated scepticism that only a concerted effort to attempt to explain will rectify. Without these explanations, it is unlikely that this knowledge will translate into the clinical arena. In the present review, we show that many of the previous concerns in the field have been addressed, but we also argue that a considerable amount of careful thought is still required to achieve enlightenment with respect to the role of RAS genes in hypertension. We discuss whether the previously identified problems of poor study design have been completely addressed with regards to the impact of ACE and AGT genes on BP. In the context of RAS genes, we also question whether the significance of ‘incomplete penetrance’ through associated environmental, phenotypic or physiological effects has been duly accounted for; whether appropriate consideration has been given to epistatic interactions between genes; and whether future RAS gene studies should consider variation across the gene by evaluating ‘haplotypes’.

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