Abstract 170: MuRF, E3 Ubiquitin Ligase, is a Negative Regulator of Cardiac Hypertrophy and Apoptosis
Muscle specific RING finger protein (MuRF1) is a sarcomere-associated protein that is expressed in cardiac and skeletal muscle. MuRF1 acts as an E3-ubiquitin ligase and is up-regulated by conditions that provoke atrophy in skeletal muscle. Limb muscle degeneration during atrophy is reduced in MuRF-1 deficient mice, suggesting that MuRF-1 plays a critical role in mediating atrophy of striated muscle through activation of the ubiquitin-proteasome pathway. Although we have previously shown that the proteasome activity is increased during cardiac hypertrophy, the function of MuRF-1 in hearts is not well understood. Interestingly, mRNA expression of MuRF-1 in the heart was significantly upregulated (3.0 fold, p<0.05) by thoracic aortic constriction (TAC) for 1 week. We therefore investigated whether MuRF-1 is involved in the progression of heart failure following cardiac pressure overload, using MuRF-1 KO mice. Left ventricular ejection fraction (LVEF) and LV wall thickness were similar between MuRF-1 KO and wild-type (WT) mice at baseline. Also after two weeks of TAC, the pressure gradient was similar between the two groups. However, in the TAC group, both left ventricular (LV) septum and posterior wall thickness were significantly greater in MuRF-1 KO than in WT mice (1.60 vs 1.35 mm, p<0.05; 1.15 vs 0.97 mm, p<0.05). LV weight/body weight (BW) and lung weight/BW were significantly greater in KO than in WT mice (7.00 vs 5.22, p<0.05; 6.78 vs 6.17, p<0.05). mRNA expression of ANF and α-skeletal actin was also significantly greater in KO than in WT mice (p<0.05). Although there was no significant difference in systolic function between KO and WT mice, LVEDP was elevated in KO compared with WT mice (7.8 vs 4.3 mmHg). Furthermore, Masson’s Trichrome staining of LV sections revealed significantly enhanced interstitial fibrosis in KO after TAC. These results suggest that MuRF1 is upregulated in response to pressure overload and that the lack of MuRF1 enhances cardiac hypertrophy and interstitial fibrosis, thereby facilitating cardiac dysfunction. In conclusion, these results indicate that MuRF-1 is a negative regulator of cardiac hypertrophy and possibly plays a protective role against progression of congestive heart failure.