RAAS Blockade and COVID‐19: Mechanistic Modeling of Mas and AT1 Receptor Occupancy as Indicators of Pro‐Inflammatory and Anti‐Inflammatory Balance

Abstract

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 proinflammatory shifts in the mas-AT1 ratio due to ACE2 downregulation by SARS-CoV-2 were small relative to antiinflammatory 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. Hypertension and diabetes are common comorbidities among hospitalized patients with coronavirus disease 2019 (COVID-19). 1 ACE inhibitors (ACEis) and angiotensin receptor blockers (ARBs) are standard of care treatment for these comorbidities, because they reduce cardiovascular events, kidney injury, and other vascular complications of these diseases. 2,3 There has been a good deal of

Angiotensin converting enzyme (ACE) 1 expression in leukocytes of adults from 64 to 67 years old

“…Recently it was shown that the membrane-bound ACE2 acts as a receptor for SARS-CoV-2 but it is still under investigation the possible effects on RAS components (AngII, Ang1-7, ACE, ACE2, AT1 and Mas) and whether ACEi and ARBs interfere with the mitigation of COVID-19. [35, 36, 37, 38, 39] Considered that COVID-19 and other infectious diseases have a major impact in aged adults, mainly in those with chronic diseases (i.e. hypertension and users of ACEi or ARBs), our results bring new intriguing questions regarding the link between ACE expression in immune cells, inflammaging and immunosenescence and perspectives for drug development/repurposing.…”

“…Recently it was shown that the membrane-bound ACE2 acts as a receptor for SARS-CoV-2 but it is still under investigation the possible effects on RAS components (AngII, Ang1-7, ACE1, ACE2, AT1 and Mas) and whether ACEi and ARBs interfere with the mitigation of COVID-19. [50, 51, 52, 53, 54] Therefore, it is important to emphasize the negative impact of chronic diseases for the outcome of older adults during a viral infection and how ACE1/ACE2 expression in immune cells could bring information to diagnosis and treatment.…”

Perspectives of (/memorandum for) systems thinking on COVID‐19 pandemic and pathology

“… 88 , 89 It is the result of high affinity of SARS‐CoV2 to critical components of the ACE2 axis compared to the AT1 receptor axis, resulting in a hyperinflammatory state of RAAS. 90 , 91 , 92 , 93 Physiologically, it should be noted that the RAAS belongs to the blood pressure controlling part of the endocrine system; but it also has these effects on inflammation. Integrating RAAS into the conceptualisation of the immune system with its pro‐ and anti‐inflammatory functions and its innate and adaptive cellular components in the view of a systemic functional analysis leads to a network model with imbalanced interactions, resulting in a hyper‐inflammatory state of the cellular matrix (Figure 3 ).…”

ACE2 and Innate Immunity in the Regulation of SARS-CoV-2-Induced Acute Lung Injury: A Review

“…Neyrinck et al [ 184 ] demonstrated that ACEI had a therapeutic effect on endotoxin-induced lung injury in rats. Melissa et al [ 185 ] showed that ACEI and ARBs might improve ARDS by inhibiting the ACE/Ang II/AT1R signaling pathway. ARBs inhibited the canonical RAS pathway through angiotensin /Ang II/ATR1 axis; increasing ACE2, TLR-2, and IL-1β; and causing accumulation of reactive oxygen species (ROS), while ACE2 upregulation activates Ang-(1-7)/Mas pathway and inhibits inflammatory signals [ 186 ].…”