| First Author | Usui S | Year | 2011 |
| Journal | Circ Res | Volume | 109 |
| Issue | 2 | Pages | 161-71 |
| PubMed ID | 21617130 | Mgi Jnum | J:185682 |
| Mgi Id | MGI:5429654 | Doi | 10.1161/CIRCRESAHA.110.238717 |
| Citation | Usui S, et al. (2011) Endogenous muscle atrophy F-box mediates pressure overload-induced cardiac hypertrophy through regulation of nuclear factor-kappaB. Circ Res 109(2):161-71 |
| abstractText | RATIONALE: Overexpression of muscle atrophy F-box (MAFbx/atrogin-1), an E3 ubiquitin ligase, induces proteasomal degradation in cardiomyocytes. The role of endogenous MAFbx in regulating cardiac hypertrophy and failure remains unclear. Objective: We investigated the role of MAFbx in regulating cardiac hypertrophy and function in response to pressure overload. Transverse aortic constriction (TAC) was applied to MAFbx knockout (KO) and wild-type (WT) mice. METHODS AND RESULTS: Expression of MAFbx in WT mice was significantly increased by TAC. TAC-induced increases in cardiac hypertrophy were significantly smaller in MAFbx KO than in WT mice. There was significantly less lung congestion and interstitial fibrosis in MAFbx KO than in WT mice. MAFbx KO also inhibited beta-adrenergic cardiac hypertrophy. DNA microarray analysis revealed that activation of genes associated with the transcription factor binding site for the nuclear factor-kappaB family were inhibited in MAFbx KO mice compared with WT mice after TAC. Although the levels of IkappaB-alpha were significantly decreased after TAC in WT mice, they were increased in MAFbx KO mice. MAFbx regulates ubiquitination and proteasomal degradation of IkappaB-alpha in cardiomyocytes. In primary cultured rat cardiomyocytes, phenylephrine-induced activation of nuclear factor-kappaB and hypertrophy were significantly suppressed by MAFbx knockdown but were partially rescued by overexpression of nuclear factor-kappaB p65. CONCLUSIONS: MAFbx plays an essential role in mediating cardiac hypertrophy in response to pressure overload. Downregulation of MAFbx inhibits cardiac hypertrophy in part through stabilization of IkappaB-alpha and inactivation of nuclear factor-kappaB. Taken together, inhibition of MAFbx attenuates pathological hypertrophy, thereby protecting the heart from progression into heart failure. |
