Correcting the imbalanced protective RAS in COVID-19 with angiotensin AT2-receptor agonists

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that is responsible for the global corona virus disease 2019 (COVID-19) pandemic enters host cells via a mechanism that includes binding to angiotensin converting enzyme (ACE) 2 (ACE2). Membrane-bound ACE2 is depleted as a result of this entry mechanism. The consequence is that the protective renin–angiotensin system (RAS), of which ACE2 is an essential component, is compromised through lack of production of the protective peptides angiotensin-(1-7) and angiotensin-(1-9), and therefore decreased stimulation of Mas (receptor Mas) and angiotensin AT2-receptors (AT2Rs), while angiotensin AT1-receptors (AT1Rs) are overstimulated due to less degradation of angiotensin II (Ang II) by ACE2. The protective RAS has numerous beneficial actions, including anti-inflammatory, anti-coagulative, anti-fibrotic effects along with endothelial and neural protection; opposite to the deleterious effects caused by heightened stimulation of angiotensin AT1R. Given that patients with severe COVID-19 exhibit an excessive immune response, endothelial dysfunction, increased clotting, thromboses and stroke, enhancing the activity of the protective RAS is likely beneficial. In this article, we discuss the evidence for a dysfunctional protective RAS in COVID and develop a rationale that the protective RAS imbalance in COVID-19 may be corrected by using AT2R agonists. We further review preclinical studies with AT2R agonists which suggest that AT2R stimulation may be therapeutically effective to treat COVID-19-induced disorders of various organ systems such as lung, vasculature, or the brain. Finally, we provide information on the design of a clinical trial in which patients with COVID-19 were treated with the AT2R agonist Compound 21 (C21). This trial has been completed, but results have not yet been reported.

Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers: potential allies in the COVID-19 pandemic instead of a threat?

“…Considering the other side of the coin, ACEI/ARB might potentially be of benefit. They reduce the deleterious effects of Ang II and support ACE2-mediated conversion of Ang II into Ang 1-7 or Ang I to Ang 1-9; both alternative angiotensins attenuate inflammation and proliferation via Mas or AT2 receptor stimulation [6,11]. Furthermore, splitting thymosin β4 with prolyl oligopeptidase gives rise to N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), which exerts a beneficial effect on tissue structure by direct actions curbing inflammation and excessive fibrosis in the heart, vessels and kidney.…”

“…The outbreak of the COVID-19 pandemic has not only afflicted everyday life at manifold levels but also introduced novel therapeutic challenges [5,6]. Unfortunately, a number of clinical trials testing antiviral, anti-inflammatory and immunomodulatory substances have brought more disappointment than delight.…”

“…On the one hand, ACE2 transforms Ang II to Ang 1-7 with an anti-inflammatory nature. On the other hand, ACE2 is a binding receptor and entry route for SARS-CoV-2 [6,8,9]. Since the findings of experimental studies indicated that ACEI/ARB increased cellular membrane-bound ACE2 (mACE2) expression, opinions have emerged about whether ACEI/ARB may heighten susceptibility to SARS-CoV-2 infection and worsen its prognosis; thus, the justification of renin-angiotensin system (RAS) inhibition in COVID-19 patients was addressed [10].…”

Brain angiotensin system: a new promise in the management of epilepsy?

“…As a side note, the prominent role of ACE2 as viral spike receptor in the present SARS-CoV-2 pandemic has raised a number of hypotheses concerning the potential role of RAS in the neuroinflammation and neurological alterations in COVID-19 affected patients. Present hypotheses propose that virus entrance to cells dramatically depletes ACE2 and thus decreases beneficial Ang-(1-7)/MasR activity and increases the detrimental Ang II/ATR1 pathway in different organs, including the brain (see as examples [21,22,25]; Figure 1B).…”

“…Ang II binds to ATR1 and promotes vascular contractility, inflammation and oxidative stress; while Ang-(1-7), produced by ACE2, activates MasR and counteracts the effects of the Ang II/AT1R axis (see revision in [20]). Counteracting the Ang II/ATR1 effects, the activation of brain Ang-(1-7)/MasR pathway produces beneficial effects for neuronal survival such as vasodilatation, anti-inflammation, antioxidant, and activates anti-apoptotic pathways (reviewed in [21,22,23,24]; Figure 1B). The role of RAS in neuroinflammation, and specifically the balance of ATR1/MasR, is critical.…”