Genetic deletion of MrgD receptor increased left ventricular mass by 12.35% (p<0.05), caused cardiac atrophy with 13.27% thinner LV wall and 26.14% smaller cardiomyocyte area, elevated collagen deposition (up to 209%), increased pro-oxidative and ER stress markers, and activated ubiquitin-proteasome protein degradation pathway in male mice at 16 weeks.
Does genetic deletion of the MrgD receptor disrupt cardiac protein homeostasis and morphology in mice?
Genetic deletion of the MrgD receptor in mice promotes cardiac atrophy, fibrosis, and disrupts protein homeostasis via increased ER stress and ubiquitin-proteasome pathway activation.
Effect estimate: +12.35% increase in LV mass (p<0.05)
Absolute Event Rate: 103.7% vs 92.3%
p-value: p=<0.05
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. 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. 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. 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.
Alexandre-Santos et al. (Sat,) conducted a other in 16-week-old male C57BL/6J mice with genetic deletion of MrgD receptor versus wild-type controls (n=20). Genetic deletion of MrgD receptor vs. Wild-type mice was evaluated on Cardiac morphology and protein homeostasis markers including LV mass, LV wall thickness, cardiomyocyte cross-sectional area, collagen deposition, pro-oxidative markers, ER stress markers, and ubiquitin-proteasome pathway activation (+12.35% increase in LV mass (p<0.05), p=<0.05). Genetic deletion of MrgD receptor increased left ventricular mass by 12.35% (p<0.05), caused cardiac atrophy with 13.27% thinner LV wall and 26.14% smaller cardiomyocyte area, elevated collagen deposition (up to 209%), increased pro-oxidative and ER stress markers, and activated ubiquitin-proteasome protein degradation pathway in male mice at 16 weeks.