Game of "crowning" season 8: RAS and reproductive hormones in COVID-19 - can we end this viral series?

Abstract

The outbreak of a newly identified coronavirus, the SARS-CoV-2 (alternative name 2019-nCoV), capable of jumping across species causing zoonosis with severe acute respiratory syndromes (SARS), has alerted authorities worldwide. Soon after the epidemic was first detected in the city of Wuhan in the Hubei Province of China, starting in late December 2019, the virus spread over multiple countries in different continents, being declared a pandemic by March 2020. The demographic characteristics of the infected patients suggest that age, sex, and comorbidities are predictive factors for the fatality of the infection. The mechanisms of viral entry into the human host cells seem to be in a close relationship with the mechanisms of regulating the renin-angiotensin system (RAS), which may explain the pathogenesis associated with the infection. This brings new insights into the possibilities of exploiting viral entry mechanisms to limit associated complications by means of enhancing the resistance of the infected patients using methods of regulating the RAS and strategies of modulating ACE2 expression. In this perspective article we exploit the mechanisms of COVID-19 pathogenesis based on the demographic characteristics of the infected patients reported in the recent literature and explore several approaches of limiting the initial steps of viral entry and pathogenesis based on viral interactions with ACE2 and RAS. We further discuss the implications of reproductive hormones in the regulation of the RAS and investigate the premise of using endocrine therapy against COVID-19.

Keywords: 2019-nCoV; ACE2; ADAM-17; ARBs; COVID-19; SARS-CoV-2; endocrine therapy; miRNA; mineralocorticoid receptor antagonist.

Figure 1

Schematic representation of the binding site for SARS-CoV2. Spike glycoproteins S on the viral surface bind to ACE2 on human cell surface, leading to internalisation of the virus into the host cell

Figure 2

Competitive mechanisms involving viral entry into host cells and RAS regulation through ACE2. Physiological mechanisms of regulating the renin-angiotensin system involve the pressor pathway (ACE/Ang II/AT1R) and the counteracting arm – the depressor pathway (ACE2/Ang 1-7/MasR and AT2R). The new coronavirus (SARS-CoV-2) exploits ACE2 to ensure viral entry into host cells, antagonising the counteracting arm of the RAS system. This leads to complications associated with exacerbation of the ACE/Ang-II/AT1R axis, as has been observed in the pathogenesis of COVID-19. Possible strategies of limiting viral entry and pathogenesis involve modulating ACE2 expression and regulating the counteracting arm of the RAS system shifting the balance towards the ACE2/Ang 1-7/MasR and AT2R axis

Figure 3

Schematic representation of the mechanism of viral entry into the lung cells by exploiting ACE2 and epitheliasin (TMPRSS2). SARS-CoV-2 enters the lung cells following the binding with the ACE2 and the activation of the fusion peptide in the spike protein by the membrane protease TMPRSS2. Androgen deprivation therapy decreases TMPRSS2 expression inhibiting the mechanisms of exploiting epitheliasin for the activation of the spike