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 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.

Figure 1

The renin‐angiotensin system and (a) Schematic representation of renin‐angiotensin system (RAAS) mathematical model. Equations for each rate reaction are given in Table  S2 . The RAAS system illustrated in schematically in a can be represented mathematically as a set of processes summarized in (b), and the reaction rates A–G are given in Table  S2 . Each enzyme reaction in this system is assumed to follow Michaelis‐Menten kinetics (Eq. 1) with a Michaelis constant K _m defined by Eq. 2. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 2

Simulated effects of changes in ACE2 concentration, with and without ARB or ACEi treatment on (a) mas‐AT1 receptor occupancy ratio, (b) mas receptor occupancy, (c) AT1 receptor occupancy, and (d) AT2 receptor occupancy. Gray dashed line is the “normal” ACE2 level. All values are standardized by their value at normal ACE2 in the absence of ARB/ACEi therapy. ACEi, ACE inhibitor; ARB, angiotensin receptor blocker.

Figure 3

Parameter sensitivity of changes in receptor occupancy with (a) a change in ACE2 with no therapy, (b) initiation of ACE inhibition, and (c) initiation of ARB inhibition. Brightest colors indicate highest correlation between parameter and receptor occupancy. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 4

Simulated effect of ACE2 downregulation by severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) infection on (a) mas occupancy, (b) AT1 occupancy, and (c) mas‐AT1 ratio, in a population of virtual patients with variable ACE, ACE2, NEP, and renin expression. Points represent simulations outside the interquartile range. Viral downregulation of ACE2 is predicted to decrease mas and increase AT1 binding, but the magnitude of the effect is small relative to the opposing effects of background therapy with ACEis and ARBs, which elevate mas and decrease AT1 occupancy. ACEis, ACE inhibitors; ARBs, angiotensin receptor blockers; COVID‐19, coronavirus disease 2019.

Figure 5

Simulated changes in Ang(1‐7) production rate (bars) with ACEi or ARB treatment, and with infection‐induced ACE2 downregulation, are small relative to rates of Ang(1‐7) infusion rates found to elicit protection from lung injury in experimental models (dashed lines ¹⁶ , ³⁹ , ⁴⁰ ). ACEi, ACE inhibitor; Ang, angiotensin; ARB, angiotensin receptor blocker; COVID‐19, coronavirus disease 2019.