Activation of the Mas receptors by AVE0991 and MrgD receptor using alamandine to limit the deleterious effects of Ang II‐induced hypertension

Abstract

The MrgD receptor agonist, alamandine (ALA) and Mas receptor agonist, AVE0991 have recently been identified as protective components of the renin‐angiotensin system. We evaluated the effects of ALA and AVE0991 on cardiovascular function and remodeling in angiotensin (Ang) II‐induced hypertension in rats. Sprague Dawley rats were subject to 4‐week subcutaneous infusions of Ang II (80 ng/kg/min) or saline after which they were treated with ALA (50 μg/kg), AVE0991 (576 μg/kg), or ALA+AVE0991 during the last 2 weeks. Systolic blood pressure (SBP) and heart rate (HR) values were recorded with tail‐cuff plethysmography at 1, 15, and 29 days post‐treatment. After euthanization, the heart and thoracic aorta were removed for further analysis and vascular responses. SBP significantly increased in the Ang II group when compared to the control group. Furthermore, Ang II also caused an increase in cardiac and aortic cyclophilin‐A (CYP‐A), monocyte chemoattractant protein‐1 (MCP‐1), and cardiomyocyte degeneration but produced a decrease in vascular relaxation. HR, matrix metalloproteinase‐2 and ‐9, NADPH oxidase‐4, and lysyl oxidase levels were comparable among groups. ALA, AVE0991, and the drug combination produced antihypertensive effects and alleviated vascular responses. The inflammatory and oxidative stress related to cardiac MCP‐1 and CYP‐A levels decreased in the Ang II+ALA+AVE0991 group. Vascular but not cardiac angiotensin‐converting enzyme‐2 levels decreased with Ang II administration but were similar to the Ang II+ALA+AVE0991 group. Our experimental data showed the combination of ALA and AVE0991 was found beneficial in Ang II‐induced hypertension in rats by reducing SBP, oxidative stress, inflammation, and improving vascular responses.

Differential changes in end organ immune cells and inflammation in salt-sensitive hypertension: effects of increasing M2 macrophages

“…This indicates that while AVE treatment may partially mitigate the HTN phenotype associated with SSHTN, it does not fully normalize BP. Overall, these findings highlight the potential therapeutic benefit of AVE in reducing SBP levels in SSHTN, albeit with some limitations that warrant further investigation and optimization of treatment, like combination therapies, or additional interventions as described in previous studies [ 50 ].…”

Novel aspects of the renin-angiotensin system for pulmonary arterial hypertension

“…While AVE0991 is a non-peptide and orally active compound that has protective effects on the vessels, kidneys, and heart by binding to the Mas receptor, Alamandine is formed as a result of decarboxylation of the Asp1 residue from Ang (1-7) to the Ala1 residue at the N-terminus. Alamandine exerts its vasodilatory and antifibrotic effects similar to Ang (1-7) through MrgD (Mas-related G protein coupled receptor D) [13]. In the present study, the authors have detected that the gene expression level of AT2R did not change significantly throughout the whole experiment.…”

Counter-regulatory RAS peptides: new therapy targets for inflammation and fibrotic diseases?

“…However, there was an accumulation of cells still present ( Zhou et al, 2019 ). In another study of Ang II-induced hypertension in rats, AVE treatment in combination with alamandine reduced inflammatory stress related to the increase in MCP-1 ( Tanrıverdi et al, 2023 ).…”