MuRF2 regulates PPARγ1 activity to protect against diabetic cardiomyopathy and enhance weight gain induced by a high fat diet

摘要: In diabetes mellitus the morbidity and mortality of cardiovascular disease is increased represents an important independent mechanism by which heart exacerbated. The pathogenesis diabetic cardiomyopathy involves enhanced activation PPAR transcription factors, including PPARα, to a lesser degree PPARβ PPARγ1. How these factors are regulated in largely unknown. Recent studies have described post-translational ubiquitination PPARs as ways activity inhibited cancer. However, specific mechanisms not previously been described. implicated muscle-specific ubiquitin ligase muscle ring finger-2 (MuRF2) inhibiting nuclear factor SRF. Initial MuRF2−/− hearts revealed activity, leading hypothesis that MuRF2 regulates ubiquitination. mice were challenged with 26-week 60% fat diet designed simulate obesity-mediated insulin resistance cardiomyopathy. Mice followed conscious echocardiography, blood glucose, tissue triglyceride, glycogen levels, immunoblot analysis intracellular signaling, skeletal morphometrics, PPARβ, PPARγ1-regulated mRNA expression. protein levels increase ~20% during development induced high diet. Compared littermate wildtype hearts, exhibit exaggerated cardiomyopathy, characterized early onset systolic dysfunction, larger left ventricular mass, higher weight. had significantly PPARα- gene expression RT-qPCR, consistent MuRF2’s regulation vivo. Mechanistically, mono-ubiquitinated PPARα PPARγ1 vitro, its non-degradatory role increasing MuRF2:PPARγ1 (>5:1) beyond physiological drove poly-ubiquitin-mediated degradation indicating large increases may lead if found other states. Mutations contribute severity familial hypertrophic present study suggests lack MuRF2, patients, can result These also identify first regulate cardiac activities vivo via modification without degradation.