Abstract
BACKGROUND: Cardiovascular diseases are the leading cause of death worldwide. An important mechanism involved is the disruption in protein homeostasis by overactivation of the classical axis of the renin-angiotensin system. The counterregulatory axis counteracts these effects; however, the MrgD receptor has recently been described, and its effects are unknown. Thus, this study aims to evaluate the impact of MrgD deficiency on cardiac protein homeostasis. METHODS: 16-week-old wild-type (WT) and MrgD knockout (MrgD KO) male C57BL/6J mice were evaluated for systolic blood pressure (SBP), cardiac morphology, MDA levels, carbonyl content, and protein homeostasis markers. RESULTS: SBP and heart mass remained unaltered. MrgD deficiency increased left ventricular mass and led to cardiac atrophy by reduced left ventricular wall thickness and cardiomyocyte cross-sectional area. Collagen (types 1 and 3) deposition and MMP-2 cardiac protein expression were elevated in MrgD KO. Genetic deletion of MrgD increased NOX2, NOX4, and ERO1α cardiac protein expression. MDA levels were similar between groups, and carbonyl content was higher in MrgD KO. GRP78, CHOP, MuRF-1, Atrogin-1, and polyubiquitinated proteins were increased in MrgD KO mice, indicating a loss of protein homeostasis. CONCLUSIONS: The genetic deletion of MrgD promoted cardiac remodeling and disrupted protein homeostasis, with increased pro-oxidative response and ER stress. This was associated with protein degradation by the activation of the ubiquitin-proteasome pathway. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11033-026-11639-8.