The influence of renin angiotensin aldosterone system (RAAS), endothelial nitric oxide synthase (eNOS) and erythropoietin (EPO) on COVID-19 complications

Abstract

Certain aspects of the renin-angiotensin-aldosterone system (RAAS) have eluded deserved attention such as the role of erythropoietin (EPO) and nitric oxide (NO) both of which appear to significantly modulate COVID-19 disease course. Furthermore, renin-angiotensin-aldosterone system (RAAS) and endothelial NO synthase (eNOS) genetic polymorphisms additionally impact on EPO and NO homeostasis and have extensive implications on pharmacological disease management.

Beauty and the beast: host microRNA-155 versus SARS-CoV-2

“…Evidently, Ang II-induced EPO production persists even when AT1R signaling is disrupted. Presumably, additional mechanisms preserving EPO formation come to play, such as hemodynamic effects and tissue oxygenation of EPO-producing cells, ALD via the mineralocorticoid receptor (MR), direct Ang II and ALD effects on hypoxia-inducible factor (HIF)-1α that induce EPO gene transcription, and compensatory Ang II activation of the AT2R [2,33,34,[61][62][63][64]. It is, thus, obvious that, RAAS regulation of EPO involves a summation of interconnecting mechanisms, and not exclusively Ang II/ AT1R signaling.…”

“…1, 2) and ACE2 is subsequently downregulated [102]. An immediate ACE1/ACE2 imbalance ensues, that strongly engages host humoral and tissue RAAS, leading to enhanced Ang II and ALD formation, while the protective arm of the RAAS is rendered void [2,4]. As AT1R's level of expression, defines the biological efficacy of Ang II and thus the degree of RAAS hyperactivity, miR-155's robust AGTR1/AT1R-mRNA repression will reduce AT1R expression and membrane presence and blunt Ang II action through AT1R [70,82,103].…”

“…Severe acute respiratory coronavirus 2 (SARS-CoV-2) infection causing coronavirus disease 2019 (COVID-19) emerged in the markets of Wuhan, People's Republic of China in late 2019, and has since had the world in its grip in an unprecedented pandemic, challenging human health and economies [1]. COVID-19 demonstrates a highly variable and unpredictable course; asymptomatic or subclinical in some, inexplicably culminating into a catastrophic hyperinflammation and rapidly progressing to a potentially lethal cytokine storm in others, demanding sophisticated resources from strained health care systems [2]. Co-morbidities associated with chronic inflammatory states such as old age, smoking, hypertension, obesity, diabetes mellitus (DM), and cardiovascular disease (CVD), along with male gender, perilously predispose towards such unfortunate progression [2,3].…”

“…COVID-19 demonstrates a highly variable and unpredictable course; asymptomatic or subclinical in some, inexplicably culminating into a catastrophic hyperinflammation and rapidly progressing to a potentially lethal cytokine storm in others, demanding sophisticated resources from strained health care systems [2]. Co-morbidities associated with chronic inflammatory states such as old age, smoking, hypertension, obesity, diabetes mellitus (DM), and cardiovascular disease (CVD), along with male gender, perilously predispose towards such unfortunate progression [2,3]. Certain host attributes predict a severe course and impending lethality while various genetic determinants, environmental elements, geography, lifestyle behaviors, and early age, may engender SARS-CoV-2 protection [4,5].…”

“…We have put forward an evolutionary congruent, mechanistical explanation accounting for the interaction between host and SARS-CoV-2, that involves an early age, erythropoietin (EPO)-dependent, protective evolutionary landscape [2,4,5,30]. Such an ancestral, protective EPO evolutionary landscape provides the host with a fitness advantage, forming constraints against pathogen adaptation and invasion [31,32].…”