The highly-regulated renin-angiotensin-aldosterone system (RAAS) has a key role in maintaining haemostasis in haemodynamic, inflammatory and fibrotic processes. The virus responsible for COVID-19, SARS-CoV-2, appears to hijack and deregulate the RAAS. Specifically, it binds to and downregulates molecules that protect the lung. These effects can be mitigated in animal models by widely available medications, the angiotensin receptor blockers (ARBs).
The RAAS system includes two cross-regulating axes: the vasoconstrictive, pro-inflammatory, pro-fibrotic ACE-Ang II-AT1R axis, and the vasodilatory, anti-inflammatory, anti-fibrotic ACE2-Ang1-7-MasR and ACE2-Ang1-9-AT2R axis. The ACE-Ang II-AT1R axis is associated with many non-communicable chronic disease states, an antagonism of the axis with AT1R blockers (ARBs) reduces cardiovascular events, including heart failure and the progression of chronic kidney disease.
The aetiological agent of COVID-19, SARS-CoV-2, is a newly-emerged coronavirus which is related to the SARS-CoV virus that caused the SARS epidemic in 2003. Like SARS-CoV, the Spike protein of SARS-CoV-2 appears to bind to the extracellular portion of membrane-bound ACE2, which is followed by the viral-ACE2 complex becoming internalised into the cell. Membrane-bound ACE2 has a protective role in acute respiratory failure, through its anti-inflammatory and anti-fibrotic actions. SARS-CoV reduces membrane-bound ACE2 through a number of processes that are all mediated by the AT1R in the non-COVID-19 setting, including down-regulation of cellular expression of ACE2, promotion of ADAM17-mediated cleavage of the extracellular portion of ACE2 and promotion of ACE2 internalisation. The down-regulation of SARS-CoV-2’s receptor portal of cellular entry is analogous to HIV which downregulates CC receptors – possibly to avoid super-infection. These effects alone appear sufficient to cause respiratory failure as demonstrated in animal models that only utilised the Spike protein and no replicating virus. SARS-CoV-2 has been less extensively studied but what is known suggests similar pathophysiology.
Thus SARS-CoV-2 appears to hijack membrane-bound ACE2 to gain entry to alveolar cells, and then by down-regulating membrane-bound ACE2, magnifies respiratory pathology.
ARBs may ameliorate the effects of SARS-CoV-2 infection by two mechanisms:
1. they reduce the AT1R-dependent internalisation of ACE2 in the normal state, and internalisation is the mechanism used by the virus to infect cells
2. they reduce the down-regulation of membrane-bound ACE2, ameliorating the respiratory failure associated with SARS-CoV-2 infection