Association between endothelial nitric oxide synthase and the renin-angiotensin-aldosterone system polymorphisms, blood pressure and training status in normotensive/pre-hypertension and hypertensive older adults: a pilot study

Silva, Roberta Fernanda da; Lacchini, Riccardo; Pinheiro, Lucas C.; Ferezin, Letícia Perticarrara; Tanus‐Santos, José Eduardo; Luizon, Marcelo R.; Dionísio, Thiago José; Santos, Carlos; Reia, Thaís Amanda; Jacomini, André Mourão; Moreno, Ana Maria Guilmo; Zago, Anderson Saranz

doi:10.1080/10641963.2021.1937202

Cited by 5 publications

(1 citation statement)

References 51 publications

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“…SNPs involving all the above-mentioned RAAS molecules, ( ACE/ACE2/AGT/AGTR1 ), while protective in malaria, have been implicated in severe adult COVID-19 outcomes (Table 2 ) [ 104 , 106 , 115 ]. Their net haplotype effect could significantly impact Ang II and EPO levels, eNOS activity, NO generation and bioavailability, perturbing NLRP3 inflammasome regulation, endothelial function, peripheral vascular resistance, and blood pressure (Table 2 ) [ 52 , 57 , 58 , 108 – 110 , 116 ].…”

Section: The No Genetic Pathway To Mis-cmentioning

confidence: 99%

A protective erythropoietin evolutionary landscape, NLRP3 inflammasome regulation, and multisystem inflammatory syndrome in children

Papadopoulos

Papadopoulou

2022

Human Cell

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The low incidence of pediatric severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and the associated multisystem inflammatory syndrome (MIS-C) lack a unifying pathophysiological explanation, impeding effective prevention and therapy. Activation of the NACHT, LRR, and PYD domains-containing protein (NLRP) 3 inflammasome in SARS-CoV-2 with perturbed regulation in MIS-C, has been reported. We posit that, early age physiological states and genetic determinants, such as certain polymorphisms of renin-angiotensin aldosterone system (RAAS) molecules, promote a controlled RAAS hyperactive state, and form an evolutionary landscape involving an age-dependent erythropoietin (EPO) elevation, mediating ancestral innate immune defenses that, through appropriate NLRP3 regulation, mitigate tissue injury and pathogen invasion. SARS-CoV-2-induced downregulation of angiotensin-converting enzyme (ACE)2 expression in endothelial cells (EC), impairment of endothelial nitric oxide (NO) synthase (eNOS) activity and downstream NO bioavailability, may promote a hyperactive RAAS with elevated angiotensin II and aldosterone that, can trigger, and accelerate NLRP3 inflammasome activation, while EPO-eNOS/NO abrogate it. Young age and a protective EPO evolutionary landscape may successfully inhibit SARS-CoV-2 and contain NLRP3 inflammasome activation. By contrast, increasing age and falling EPO levels, in genetically susceptible children with adverse genetic variants and co-morbidities, may lead to unopposed RAAS hyperactivity, NLRP3 inflammasome dysregulation, severe endotheliitis with pyroptotic cytokine storm, and development of autoantibodies, as already described in MIS-C. Our haplotype estimates, predicted from allele frequencies in population databases, are in concordance with MIS-C incidence reports in Europeans but indicate lower risks for Asians and African Americans. Targeted Mendelian approaches dissecting the influence of relevant genetic variants are needed.

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