Muscle ring finger‐1 (MuRF1) inhibits spontaneous cardiac hypertrophy induced by the PPARα agonist fenofibrate in vivo

Abstract

The cardiac ubiquitin ligase MuRF1 specifically binds with and inhibits PPARα activity in vitro. To determine the role of MuRF1 in regulating PPARα activity in vivo, MuRF1 −/− and wild type control mice (N=16) were fed the PPARα agonist fenofibrate 0.5% w/w in chow (or sham diet) for 3 weeks. Fenofibrate has been utilized therapeutically to induce cardiac hypertrophy regression in both human and animal models. After 3 weeks of treatment, MuRF1 −/−, but not wild type controls, developed a spontaneous cardiac hypertrophy as evidenced by a 45.2% increase in MuRF1 −/− left ventricular mass/tibia length (8.7 +/− 0.2 vs. 6.0 +/− 0.5 mg/mm) and a 20% increase in both anterior and posterior cardiac wall thickness. M‐mode determination of systolic function in MuRF1 −/− hearts (FS% 53.1+/−1.6) did not identify differences from wild type or baseline cardiac. MuRF1 −/−, but not wild type mice, had increased levels of βMHC (~4 fold), BNP (~1.5 fold), and smooth muscle α‐actinin (~2 fold) by Real Time PCR after fenofibrate treatment, suggesting that pathologic cardiac hypertrophy was induced in MuRF1 −/− hearts. In the absence of MuRF1, enhanced PPARα signaling leads to a spontaneous pathologic cardiac hypertrophy. These findings identify for the first time the interplay between MuRF1, PPARα, and signaling pathways that mediate pathologic cardiac hypertrophy in vivo, giving insight into PPARα's role in regulating cardiac hypertrophy.