Endogenous Muscle Atrophy F-Box Mediates Pressure Overload-Induced Cardiac Hypertrophy Through Regulation of Nuclear Factor- B

Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, UMDNJ, New Jersey Medical School, Newark, NJ, USA.
Circulation Research (Impact Factor: 11.02). 05/2011; 109(2):161-71. DOI: 10.1161/CIRCRESAHA.110.238717
Source: PubMed


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.
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 β-adrenergic cardiac hypertrophy. DNA microarray analysis revealed that activation of genes associated with the transcription factor binding site for the nuclear factor-κB family were inhibited in MAFbx KO mice compared with WT mice after TAC. Although the levels of IκB-α were significantly decreased after TAC in WT mice, they were increased in MAFbx KO mice. MAFbx regulates ubiquitination and proteasomal degradation of IκB-α in cardiomyocytes. In primary cultured rat cardiomyocytes, phenylephrine-induced activation of nuclear factor-κB and hypertrophy were significantly suppressed by MAFbx knockdown but were partially rescued by overexpression of nuclear factor-κB p65.
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 IκB-α and inactivation of nuclear factor-κB. Taken together, inhibition of MAFbx attenuates pathological hypertrophy, thereby protecting the heart from progression into heart failure.

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    • "The precise role of the Foxo1-MAFbx/MuRF1 axis in cardiac muscle is less clearly defined than it is in skeletal muscle. In contrast to its clearly defined role as a driver of atrophy in skeletal muscle, both MAFbx and MuRF1 are drivers of overload-induced cardiac hypertrophy [35], [36]. However, others have described a catabolic role for MAFbx, where overexpression in myocardium prevents Akt-induced hypertrophy [37]. "
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