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Clin Pharmacol Ther ; 109(4): 1092-1103, 2021 04.
Article in English | MEDLINE | ID: covidwho-1051200


ACE inhibitors (ACEis) and angiotensin receptor blockers (ARBs) are standard-of-care treatments for hypertension and diabetes, common comorbidities among hospitalized patients with coronavirus disease 2019 (COVID-19). Their use in the setting of COVID-19 has been heavily debated due to potential interactions with ACE2, an enzyme that links the pro-inflammatory and anti-inflammatory arms of the renin angiotensin system, but also the entryway by which severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) invades cells. ACE2 expression is altered by age, hypertension, diabetes, and the virus itself. This study integrated available information about the renin angiotensin aldosterone system (RAAS) and effects of SARS-CoV-2 and its comorbidities on ACE2 into a mechanistic mathematical model and aimed to quantitatively predict effects of ACEi/ARBs on the RAAS pro-inflammatory/anti-inflammatory balance. RAAS blockade prior to SARS-CoV-2 infection is predicted to increase the mas-AT1 receptor occupancy ratio up to 20-fold, indicating that in patients already taking an ACEi/ARB before infection, the anti-inflammatory arm is already elevated while the pro-inflammatory arm is suppressed. Predicted pro-inflammatory shifts in the mas-AT1 ratio due to ACE2 downregulation by SARS-CoV-2 were small relative to anti-inflammatory shifts induced by ACEi/ARB. Predicted effects of changes in ACE2 expression with comorbidities of diabetes, hypertension, or aging on mas-AT1 occupancy ratio were also relatively small. Last, predicted changes in the angiotensin (Ang(1-7)) production rate with ACEi/ARB therapy, comorbidities, or infection were all small relative to exogenous Ang(1-7) infusion rates shown experimentally to protect against acute lung injury, suggesting that any changes in the ACE2-Ang(1-7)-mas arm may not be large enough to play a major role in COVID-19 pathophysiology.

Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , COVID-19/physiopathology , Receptor, Angiotensin, Type 1/physiology , Renin-Angiotensin System/physiology , Age Factors , Aging/physiology , Diabetes Mellitus/physiopathology , Humans , Hypertension/drug therapy , Hypertension/physiopathology , Inflammation Mediators/metabolism , Models, Theoretical , SARS-CoV-2
Endocr Metab Immune Disord Drug Targets ; 20(6): 807-811, 2020.
Article in English | MEDLINE | ID: covidwho-689779
Kaohsiung J Med Sci ; 36(6): 389-392, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-505606


The spike glycoprotein on the virion surface docking onto the angiotensin-converting enzyme (ACE) 2 dimer is an essential step in the process of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in human cells-involves downregulation of ACE2 expression with systemic renin-angiotensin system (RAS) imbalance and promotion of multi-organ damage. In general, the RAS induces vasoconstriction, hypertension, inflammation, fibrosis, and proliferation via the ACE/Ang II/Ang II type 1 receptor (AT1R) axis and induces the opposite effects via the ACE2/Ang (1-7)/Mas axis. The RAS may be activated by chronic inflammation in hypertension, diabetes, obesity, and cancer. SARS-CoV-2 induces the ACE2 internalization and shedding, leading to the inactivation of the ACE2/Ang (1-7)/Mas axis. Therefore, we hypothesize that two hits to the RAS drives COVID-19 progression. In brief, the first hit originates from chronic inflammation activating the ACE/Ang II/AT1R axis, and the second originates from the COVID-19 infection inactivating the ACE2/Ang (1-7)/Mas axis. Moreover, the two hits to the RAS may be the primary reason for increased mortality in patients with COVID-19 who have comorbidities and may serve as a therapeutic target for COVID-19 treatment.

Betacoronavirus , Coronavirus Infections/physiopathology , Pneumonia, Viral/physiopathology , Renin-Angiotensin System/physiology , Angiotensin II/physiology , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Betacoronavirus/pathogenicity , Betacoronavirus/physiology , COVID-19 , Comorbidity , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Humans , Models, Biological , Pandemics , Peptidyl-Dipeptidase A/physiology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Receptor, Angiotensin, Type 1/physiology , Renin-Angiotensin System/drug effects , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/physiology