Biological Context Linking Hypertension and Higher Risk for COVID-19 Severity

Abstract

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents a public health crisis of major proportions. Advanced age, male gender, and the presence of comorbidities have emerged as risk factors for severe illness or death from COVID-19 in observation studies. Hypertension is one of the most common comorbidities in patients with COVID-19. Indeed, hypertension has been shown to be associated with increased risk for mortality, acute respiratory distress syndrome, need for intensive care unit admission, and disease progression in COVID-19 patients. However, up to the present time, the precise mechanisms of how hypertension may lead to the more severe manifestations of disease in patients with COVID-19 remains unknown. This review aims to present the biological plausibility linking hypertension and higher risk for COVID-19 severity. Emphasis is given to the role of the renin-angiotensin system and its inhibitors, given the crucial role that this system plays in both viral transmissibility and the pathophysiology of arterial hypertension. We also describe the importance of the immune system, which is dysregulated in hypertension and SARS-CoV-2 infection, and the potential involvement of the multifunctional enzyme dipeptidyl peptidase 4 (DPP4), that, in addition to the angiotensin-converting enzyme 2 (ACE2), may contribute to the SARS-CoV-2 entrance into target cells. The role of hemodynamic changes in hypertension that might aggravate myocardial injury in the setting of COVID-19, including endothelial dysfunction, arterial stiffness, and left ventricle hypertrophy, are also discussed.

Angiotensin (ang) 1-7 inhibits ang II-induced atrial fibrosis through regulating the interaction of proto-oncogene tyrosine-protein kinase Src (c-Src) and Src homology region 2 domain-containing phosphatase-1 (SHP-1))

“…The phosphorylation of key proteins in the MAPK pathway marks the activation and function of the signal pathway [ 28 , 29 ]. Previous studies have suggested that the Ang-(1-7)/Mas axis may negatively mediate c-Src activation including Ang II-induced downstream signals via enhancing SHP-1 activity of renal proximal convoluted tubule cells, thereby realizing the protective effect [ 29–31 32 ]. In this study, Ang-(1-7) indicated a role in improving atrial fibrosis in rats by inhibiting downstream protein kinase signaling systems ERK1/2, p38 phosphorylation, and Akt phosphorylation.…”

“…In this study, Ang-(1-7) indicated a role in improving atrial fibrosis in rats by inhibiting downstream protein kinase signaling systems ERK1/2, p38 phosphorylation, and Akt phosphorylation. c-Src inhibitors could not only restrain c-Src activation induced by Ang II, but also block Ang II action on ERK1/2, p38, and Akt signaling pathways, and SHP-1 inhibitors could also antagonize Ang-(1-7) effects on ERK1/2, p38, and Akt signaling pathways induced by Ang II [ 32 ].…”

Sex differences in the lung ACE/ACE2 balance in hypertensive rats

“…Over the last year, several reviews and opinion articles have defended the view that a disequilibrium between the classic RAS and its opposing protective arm in the lungs plays a crucial role in the pathophysiology of COVID-19 [ 19 , 22 , 23 , 42 ]. This study found that high blood pressure and male sex shift the RAS balance in the lungs towards the vasoconstrictive, profibrotic, and proinflammatory ACE/Ang II axis.…”

“…ACE2 is also the functional receptor for SARS-CoV-2 host cell entry(18), thus providing a biological link between hypertension, biological sex, and COVID-19. Loss of the ACE2 protective arm in the lungs may create an imbalance that favors the classic RAS, unleashing a cascade of harmful effects that leads to severe acute respiratory failure in COVID-19 (19)(20)(21)(22)(23). Indeed, a causal relationship between imbalance of the ACE/ACE2 axis and acute respiratory distress syndrome has been established through the use of genetically modified animals, demonstrating that the ACE/Ang II/AT1R axis drives severe acute lung failure, whereas ACE2 protects against it (24).…”

COVID-19-Patientinnen und -Patienten in Deutschland: Expositionsrisiken und assoziierte Faktoren für Hospitalisierungen und schwere Krankheitsverläufe

“…Personen mit Bluthochdruck hatten in einer Metaanalyse ein 1,46-fach erhöhtes Risiko für schwere Krankheitsverläufe (95 % KI 1,28–1,65) und ein 1,76-fach erhöhtes Risiko, zu versterben (95 % KI 1,58–1,96; [ 35 ]). Von besonderem Interesse ist in diesem Kontext das Protein Angiotensin Converting Enzyme‑2 (ACE-2), das eine Rolle bei der Regulation des Blutdrucks spielt und gleichzeitig auch der Eintrittsrezeptor für SARS-CoV‑2 in menschliche Zellen ist [ 45 ]. Zu Beginn der Pandemie war unklar, ob Personen, die antihypertensiv mit Inhibitoren des Angiotensinsystems (sog.…”