Asunto(s)
Antagonistas Adrenérgicos beta/efectos adversos , Presión Sanguínea/efectos de los fármacos , Diabetes Mellitus/prevención & control , Hipertensión/tratamiento farmacológico , Tiazidas/efectos adversos , Antagonistas Adrenérgicos beta/uso terapéutico , Aminobutiratos/farmacología , Aminobutiratos/uso terapéutico , Antagonistas de Receptores de Angiotensina/farmacología , Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Animales , Compuestos de Bifenilo/farmacología , Compuestos de Bifenilo/uso terapéutico , COVID-19/diagnóstico , COVID-19/epidemiología , COVID-19/terapia , COVID-19/virología , Bloqueadores de los Canales de Calcio/efectos adversos , Bloqueadores de los Canales de Calcio/uso terapéutico , Gatos , Diabetes Mellitus/etiología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Perros , Combinación de Medicamentos , Polipéptido Inhibidor Gástrico/efectos adversos , Polipéptido Inhibidor Gástrico/farmacología , Polipéptido Inhibidor Gástrico/uso terapéutico , Ruidos Cardíacos/fisiología , Historia del Siglo XX , Humanos , Hipertensión/complicaciones , Inmunización Pasiva/métodos , Inmunización Pasiva/estadística & datos numéricos , Incretinas/efectos adversos , Incretinas/farmacología , Incretinas/uso terapéutico , Insulina Glargina/efectos adversos , Insulina Glargina/historia , Insulina Glargina/farmacología , Insulina Glargina/uso terapéutico , Metaanálisis como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , SARS-CoV-2/genética , Tiazidas/uso terapéutico , Valsartán/farmacología , Valsartán/uso terapéutico , Sueroterapia para COVID-19RESUMEN
Men are disproportionately affected by the coronavirus disease-2019 (COVID-19), and face higher odds of severe illness and death compared to women. The vascular effects of androgen signaling and inflammatory cytokines in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-mediated endothelial injury are not defined. We determined the effects of SARS-CoV-2 spike protein-mediated endothelial injury under conditions of exposure to androgen dihydrotestosterone (DHT) and tumor necrosis factor-a (TNF-α) and tested potentially therapeutic effects of mineralocorticoid receptor antagonism by spironolactone. Circulating endothelial injury markers VCAM-1 and E-selectin were measured in men and women diagnosed with COVID-19. Exposure of endothelial cells (ECs) in vitro to DHT exacerbated spike protein S1-mediated endothelial injury transcripts for the cell adhesion molecules E-selectin, VCAM-1 and ICAM-1 and anti-fibrinolytic PAI-1 (p < 0.05), and increased THP-1 monocyte adhesion to ECs (p = 0.032). Spironolactone dramatically reduced DHT+S1-induced endothelial activation. TNF-α exacerbated S1-induced EC activation, which was abrogated by pretreatment with spironolactone. Analysis from patients hospitalized with COVID-19 showed concordant higher circulating VCAM-1 and E-Selectin levels in men, compared to women. A beneficial effect of the FDA-approved drug spironolactone was observed on endothelial cells in vitro, supporting a rationale for further evaluation of mineralocorticoid antagonism as an adjunct treatment in COVID-19.
Asunto(s)
COVID-19/patología , Dihidrotestosterona/farmacología , Endotelio Vascular/patología , Inflamación , SARS-CoV-2/fisiología , Glicoproteína de la Espiga del Coronavirus/fisiología , Espironolactona/farmacología , Antagonistas de Receptores de Angiotensina/farmacología , COVID-19/fisiopatología , COVID-19/virología , Moléculas de Adhesión Celular/sangre , Células Cultivadas , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Femenino , Humanos , Masculino , Caracteres Sexuales , Factor de Necrosis Tumoral alfa/farmacología , Factor de Necrosis Tumoral alfa/fisiología , Valsartán/farmacologíaRESUMEN
OBJECTIVE: Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) uses the host's angiotensin-converting enzyme 2 (ACE2) as a cellular entry point. Therefore, modulating ACE2 might impact SARS-CoV-2 viral replication, shedding, and coronavirus disease 2019 (COVID-19) severity. Here, it was investigated whether the angiotensin II type 1 receptor blocker valsartan alters the expression of renin-angiotensin system (RAS) components, including ACE2, in human adipose tissue (AT) and skeletal muscle. METHODS: A randomized, double-blind, placebo-controlled clinical trial was performed, in which 36 participants (BMI 31.0 ± 0.8 kg/m2 ) with impaired glucose metabolism received either valsartan or placebo for 26 weeks. Before and after 26 weeks' treatment, abdominal subcutaneous AT and skeletal muscle biopsies were obtained, and gene expression of RAS components was measured by quantitative reverse transcription polymerase chain reaction. RESULTS: Valsartan treatment did not significantly impact the expression of RAS components, including ACE2, in AT and skeletal muscle. CONCLUSIONS: Given the pivotal role of ACE2 in SARS-CoV-2 spread and the clinical outcomes in COVID-19 patients, the data suggest that the putative beneficial effects of angiotensin II type 1 receptor blockers on the clinical outcomes of patients with COVID-19 may not be mediated through altered ACE2 expression in abdominal subcutaneous AT.