Cardiovascular Damage in COVID-19: Therapeutic Approaches Targeting the Renin-Angiotensin-Aldosterone System

Abstract

Coronavirus disease 2019 (COVID-19) is usually more severe and associated with worst outcomes in individuals with pre-existing cardiovascular pathologies, including hypertension or atherothrombosis. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can differentially infect multiple tissues (i.e., lung, vessel, heart, liver) in different stages of disease, and in an age- and sex-dependent manner. In particular, cardiovascular (CV) cells (e.g., endothelial cells, cardiomyocytes) could be directly infected and indirectly disturbed by systemic alterations, leading to hyperinflammatory, apoptotic, thrombotic, and vasoconstrictive responses. Until now, hundreds of clinical trials are testing antivirals and immunomodulators to decrease SARS-CoV-2 infection or related systemic anomalies. However, new therapies targeting the CV system might reduce the severity and lethality of disease. In this line, activation of the non-canonical pathway of the renin-angiotensin-aldosterone system (RAAS) could improve CV homeostasis under COVID-19. In particular, treatments with angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-receptor blockers (ARB) may help to reduce hyperinflammation and viral propagation, while infusion of soluble ACE2 may trap plasma viral particles and increase cardioprotective Ang-(1–9) and Ang-(1–7) peptides. The association of specific ACE2 polymorphisms with increased susceptibility of infection and related CV pathologies suggests potential genetic therapies. Moreover, specific agonists of Ang-(1–7) receptor could counter-regulate the hypertensive, hyperinflammatory, and hypercoagulable responses. Interestingly, sex hormones could also regulate all these RAAS components. Therefore, while waiting for an efficient vaccine, we suggest further investigations on the non-canonical RAAS pathway to reduce cardiovascular damage and mortality in COVID-19 patients.

Insulin resistance in COVID-19 and diabetes

“…Notwithstanding that, ACE2 functions as a viral dock for entry into cells where it acts as an anti-inflammatory enzyme [ 54 ]. Therapeutic interventions with focus on stimulating the RAAS pathway has potential to enhance cardiovascular function and lower the severity of COVID-19.…”

ACE2: The Major Cell Entry Receptor for SARS-CoV-2

“…Despite having a high degree of homology with ACE, ACE2 shows a remarkable difference in substrate selection, catalyzing with high efficiency the conversion of the vasoconstrictor AngII in Ang1-7 that binds and activates its own seven-transmembrane G protein-coupled receptor (GPCR) called MAS to exert anti-inflammatory and anti-remodeling effects or, with less efficiency, the formation of Ang1-9 from AngI, which can be converted to Ang1-7 by ACE [60]. In doing so, ACE2 plays a counterbalance action in the RAAS, which is a critical regulator of blood volume and systemic vascular resistance and contributes to sodium reabsorption, inflammation, and fibrosis, preventing the possible adverse effect of AngII accumulation.…”

Renin–Angiotensin–Aldosterone System: Friend or Foe—The Matter of Balance. Insight on History, Therapeutic Implications and COVID-19 Interactions

“…Apart from RAAS inhibition, there are several future prospects for RAAS-based therapies in COVID-19. First, Mas receptor stimulation via inhibition of Ang 1-7 degradation or enhancement of its endogenous production by recombinant ACE2 is being studied in clinical trials in COVID-19 patients [ 35 , 39 , 40 ]. Second, ACE2 is assumed not only to exert anti-inflammatory actions due to Ang II conversion to Ang 1-7; sACE2 maintains its catalytic activity but loses its virus internalization capability, thus serving as a potential decoy for virus particles, preventing their binding to mACE2 and cellular invasion [ 26 , 28 ].…”