Evidence that the monoamine oxidase B (MAO-B) plays a central role in the inotropic dysfunction induced by genetic deletion of the Mas-related-G protein-coupled receptor D (MrgD) in mice

Abstract

The renin-angiotensin system (RAS) plays a critical role in the regulation of the cardiovascular system. The Mas-related G protein receptor member D (MrgD) is the receptor of alamandine, and both are components of the RAS noncanonical arm. Alamandine/MrgD induces vasodilation, anti-inflammatory, anti-fibrotic and anti-oxidative effects. In contrast, Mrgd gene deletion leads to a remarkable dilated cardiomyopathy (DCM) in mice. Here, we aimed to investigate the molecular mechanisms of DCM triggered by the deletion of MrgD in the left ventricle and isolated ventricular cardiomyocytes from 8-12 weeks old mice using phosphoproteomics. Our findings revealed an increased oxidative stress not caused by angiotensin II/AT1 hyperactivation but instead due to the up-regulation of the monoamine oxidase B (MAO-B), leading to a higher catabolism of dopamine and epinephrine in the MrgD-KO cardiac tissues. The oxidative environment induced by MAO-B hyperactivation seems to be the cause of the observed alteration in ionic dynamics - altered Ca2+ transient and Na+/K+-ATPase activity - leading to altered resting membrane potential (RMP) and decreased contraction of MrgD-KO cardiomyocytes. In addition, cardiac Troponin-I phosphorylation, and Titin dephosphorylation seem to contribute to the contractile dysfunction observed in MrgD-KO. The treatment of cardiomyocytes from MrgD-KO mice with the MAO-B inhibitor Pargyline reverted the observed impaired contraction, corroborating the hypothesis that MAO-B hyperactivation is, at least partially, the cause of the failing heart observed in MrgD-KO mouse. The findings reported here provide important insights into the pathogenesis of heart failure and suggest a potential therapeutic target (MrgD activation) for managing failing hearts.