MicroRNA-155 modulation by renin-angiotensin system inhibitors may underlie their enigmatic role in COVID-19.

Severe acute respiratory coronavirus-2 (SARS-CoV-2) infection course differs between the young and healthy and the elderly with co-morbidities. In the latter a potentially lethal coronavirus disease 2019 (COVID-19) cytokine storm has been described with an unrestrained renin-angiotensin (Ang) system (RAS). RAS inhibitors [Ang converting enzyme inhibitors and Ang II type 1 receptor (AT1R) blockers] while appearing appropriate in COVID-19, display enigmatic effects ranging from protection to harm. MicroRNA-155 (miR-155)-induced translational repression of key cardiovascular (CV) genes (i.e., AT1R) restrains SARS-CoV-2-engendered RAS hyperactivity to tolerable and SARS-CoV-2-protective CV phenotypes supporting a protective erythropoietin (EPO) evolutionary landscape. MiR-155's disrupted repression of the AT1R 1166C-allele associates with adverse CV and COVID-19 outcomes, confirming its decisive role in RAS modulation. RAS inhibition disrupts this miR-155-EPO network by further lowering EPO and miR-155 in COVID-19 with co-morbidities, thereby allowing unimpeded RAS hyperactivity to progress precariously. Current pharmacological interventions in COVID-19 employing RAS inhibition should consider these complex but potentially detrimental miR-155/EPO-related effects.