title: Endogenous muscle atrophy F-box mediates pressure overload-induced cardiac hypertrophy through regulation of nuclear factor-kappaB.
abstract: BACKGROUND
  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.
  
  
  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 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.
  
  
  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 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.
authors: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, UMDNJ, New Jersey Medical School, Newark, NJ, USA.
authors: Soichiro
authors: S
authors: Usui
authors: Yasuhiro
authors: Y
authors: Maejima
authors: Jayashree
authors: J
authors: Pain
authors: Chull
authors: C
authors: Hong
authors: Jaeyeaon
authors: J
authors: Cho
authors: Ji Yeon
authors: JY
authors: Park
authors: Daniela
authors: D
authors: Zablocki
authors: Bin
authors: B
authors: Tian
authors: David J
authors: DJ
authors: Glass
authors: Junichi
authors: J
authors: Sadoshima
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