Vascular Effects of Low-Dose ACE2 Inhibitor MLN-4760-Benefit or Detriment in Essential Hypertension?

Abstract

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infects host cells through angiotensin-converting enzyme 2 (ACE2). Concurrently, the product of ACE2 action, angiotensin 1-7 (Ang 1-7), binds to Mas receptors within the cardiovascular system and provides protective effects. Therefore, it is crucial to reveal the role of ACE2 inhibition, especially within pre-existing cardiovascular pathologies. In our study, we imitated the action of SARS-CoV-2 in organisms using the low dose of the ACE2 inhibitor MLN-4760 with the aim of investigating to what degree ACE2 inhibition is detrimental to the cardiovascular system of spontaneously hypertensive rats (SHRs), which represent a model of human essential hypertension. Our study revealed the complex action of MLN-4760 in SHRs. On the one hand, we found that MLN-4760 had (1) (pro)obesogenic effects that negatively correlated with alternative renin-angiotensin system activity and Ang 1-7 in plasma, (2) negative effects on ACE1 inhibitor (captopril) action, (3) detrimental effects on the small arteries function and (4) anti-angiogenic effect in the model of chick chorioallantoic membrane. On the other hand, MLN-4760 induced compensatory mechanisms involving strengthened Mas receptor-, nitric oxide- and hydrogen sulfide-mediated signal transduction in the aorta, which was associated with unchanged blood pressure, suggesting beneficial action of MLN-4760 when administered at a low dose.

• Authors: Andrea Berenyiova, Iveta Bernatova, Anna Zemancikova, Magdalena Drobna, Martina Cebova, Samuel Golas, Peter Balis, Silvia Liskova, Zuzana Valaskova, Katarina Krskova, Stefan Zorad, Ezgi Dayar, Sona Cacanyiova
• Journal: Biomedicines (Biomedicines) Vol. 10 Issue 1 (Dec 24 2021) ISSN: 2227-9059 [Print] Switzerland
• PMID: 35052717 (Publication Type: Journal Article)