Angiotensin I and II Stimulate Cell Invasion of SARS-CoV-2: Potential Mechanism via Inhibition of ACE2 Arm of RAS

Angiotensin-converting enzyme 2 (ACE2), one of the key enzymes of the renin-angiotensin system (RAS), plays an important role in SARS-CoV-2 infection by functioning as a virus receptor. Angiotensin peptides Ang I and Ang II, the substrates of ACE2, can modulate the binding of SARS-CoV-2 Spike protei...

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Published in:	Physiological research Vol. 73; no. 1; pp. 27 - 35
Main Authors:	Zorad, S, Skrabanova, M, Zilkova, M, Cente, M, Turic Csokova, N, Kovacech, B, Cizkova, D, Filipcik, P
Format:	Journal Article
Language:	English
Published:	Czech Republic Institute of Physiology 2024 Institute of Physiology of the Czech Academy of Sciences
Subjects:	ACE2 Angiotensin Angiotensin I Angiotensin I - metabolism Angiotensin I - pharmacology Angiotensin II Angiotensin II - metabolism Angiotensin-converting enzyme 2 Angiotensin-Converting Enzyme 2 - metabolism Angiotensin-Converting Enzyme Inhibitors Antibodies Comorbidity COVID-19 Endocrine system Enzymes Humans Infections Infectivity Metabolism Metabolites Penicillin Peptides Peptidyl-dipeptidase A Peptidyl-Dipeptidase A - metabolism Proteins Renin Renin-Angiotensin System SARS-CoV-2 - metabolism Severe acute respiratory syndrome coronavirus 2 Spike Glycoprotein, Coronavirus Spike protein Viruses
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Summary:	Angiotensin-converting enzyme 2 (ACE2), one of the key enzymes of the renin-angiotensin system (RAS), plays an important role in SARS-CoV-2 infection by functioning as a virus receptor. Angiotensin peptides Ang I and Ang II, the substrates of ACE2, can modulate the binding of SARS-CoV-2 Spike protein to the ACE2 receptor. In the present work, we found that co incubation of HEK-ACE2 and Vero E6 cells with the SARS-CoV-2 Spike pseudovirus (PVP) resulted in stimulation of the virus entry at low and high micromolar concentrations of Ang I and Ang II, respectively. The potency of Ang I and Ang II stimulation of virus entry corresponds to their binding affinity to ACE2 catalytic pocket with 10 times higher efficiency of Ang II. The Ang II induced mild increase of PVP infectivity at 20 microM; while at 100 microM the increase (129.74+/-3.99 %) was highly significant (p<0.001). Since the angiotensin peptides act in HEK ACE2 cells without the involvement of angiotensin type I receptors, we hypothesize that there is a steric interaction between the catalytic pocket of the ACE2 enzyme and the SARS-CoV-2 S1 binding domain. Oversaturation of the ACE2 with their angiotensin substrate might result in increased binding and entry of the SARS-CoV-2. In addition, the analysis of angiotensin peptides metabolism showed decreased ACE2 and increased ACE activity upon SARS-CoV-2 action. These effects should be taken into consideration in COVID-19 patients suffering from comorbidities such as the over-activated renin-angiotensin system as a mechanism potentially influencing the SARS-CoV-2 invasion into recipient cells.
Bibliography:	These authors contributed equally to this work.
ISSN:	0862-8408 1802-9973
DOI:	10.33549/physiolres.935198