Alamandine reverses hyperhomocysteinemia-induced vascular dysfunction via PKA-dependent mechanisms

Abstract

Introduction: Hyperhomocysteinemia (HHcy) impairs nitric oxide endothelium-dependent vasodilation, consequently leading to atherosclerosis, a risk factor for cardiovascular disease. Novel treatments for HHcy are necessary. Aim: We tested the hypothesis that alamandine, a vasoactive peptide of the renin-angiotensin system (RAS), could reverse HHcy-induced vascular dysfunction through the MrgD receptor and that this is mediated by the protein kinase A (PKA) pathway. Furthermore, we sought to determine a putative binding model of alamandine to the MrgD receptor through docking and molecular dynamics simulations. Method: The abdominal aorta was excised from New Zealand white rabbits (n = 15) and incubated with 3 mmol/L Hcy (to mimic HHcy) to induce vascular dysfunction in vitro. Vascular function was assessed by vasodilatory responses to cumulative doses of acetylcholine. Result: Vasodilation was significantly impaired in HHcy-incubated aortic rings while alamandine reversed this effect (control, 74.2 ± 5.0%; Hcy, 30.3 ± 9.8%; alamandine + Hcy, 59.7 ± 4.8%, P