COVID-19, vaccines and deficiency of ACE2 and other angiotensinases. Closing the loop on the "Spike effect"

Abstract

The role of a dysregulated renin-angiotensin system (RAS) in the pathogenesis of COVID-19 is well recognized. The imbalance between angiotensin II (Ang II) and Angiotensin_1-7 (Ang_1,7) caused by the interaction between SARS-CoV-2 and the angiotensin converting enzyme 2 (ACE₂) receptors exerts a pivotal role on the clinical picture and outcome of COVID-19. ACE₂ receptors are not the exclusive angiotensinases in nature. Other angiotensinases (PRCP, and POP) have the potential to limit the detrimental effects of the interactions between ACE₂ and the Spike proteins. In the cardiovascular disease continuum, ACE₂ activity tends to decrease, and POP/PRCP activity to increase, from the health status to advanced deterioration of the cardiovascular system. The failure of the counter-regulatory RAS axis during the acute phase of COVID-19 is characterized by a decrease of ACE₂ expression coupled to unchanged activity of other angiotensinases, therefore failing to limit the accumulation of Ang II. COVID-19 vaccines increase the endogenous synthesis of SARS-CoV-2 spike proteins. Once synthetized, the free-floating spike proteins circulate in the blood, interact with ACE₂ receptors and resemble the pathological features of SARS-CoV-2 ("Spike effect" of COVID-19 vaccines). It has been noted that an increased catalytic activity of POP/PRCP is typical in elderly individuals with comorbidities or previous cardiovascular events, but not in younger people. Thus, the adverse reactions to COVID-19 vaccination associated with Ang II accumulation are generally more common in younger and healthy subjects. Understanding the relationships between different mechanisms of Ang II cleavage and accumulation offers the opportunity to close the pathophysiological loop between the risk of progression to severe forms of COVID-19 and the potential adverse events of vaccination.

Keywords: ACE2; COVID-19; Olygopeptodases; POP; PRCP; Renin-angiotensin-aldosterone system; SARS-CoV-2; Therapy; Vaccines.

Fig. 1

Mechanisms implicated in the development of Angiotensin II storm during the SARS-CoV-2 infection and after vaccination. Changes in Angiotensinases levels and activities are also depicted. See text for details. Legend: A II=angiotensin II; A_1,7=angiotensin_1,7; ACE₂=angiotensin coverting enzyme 2; POP= prolyl oligopeptidase; PRCP= prolyl carboxypeptidases; RAS=renin-angiotensin system; SARS-CoV-2= severe acute respiratory syndrome coronavirus-2.