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Endogenous muscle atrophy F-box mediates pressure overload-induced cardiac hypertrophy through regulation of nuclear factor-kappaB.

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 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.

Pubmed ID: 21617130

Authors

  • Usui S
  • Maejima Y
  • Pain J
  • Hong C
  • Cho J
  • Park JY
  • Zablocki D
  • Tian B
  • Glass DJ
  • Sadoshima J

Journal

Circulation research

Publication Data

July 8, 2011

Associated Grants

  • Agency: NIA NIH HHS, Id: AG27211
  • Agency: NHLBI NIH HHS, Id: HL102738
  • Agency: NHLBI NIH HHS, Id: HL59139
  • Agency: NHLBI NIH HHS, Id: HL67724
  • Agency: NHLBI NIH HHS, Id: HL69020
  • Agency: NHLBI NIH HHS, Id: HL91469
  • Agency: NHLBI NIH HHS, Id: HL98802
  • Agency: NIA NIH HHS, Id: P01 AG027211
  • Agency: NIA NIH HHS, Id: P01 AG027211-05
  • Agency: NHLBI NIH HHS, Id: P01 HL059139
  • Agency: NHLBI NIH HHS, Id: P01 HL059139-10
  • Agency: NHLBI NIH HHS, Id: P01 HL069020
  • Agency: NHLBI NIH HHS, Id: P01 HL069020-10
  • Agency: NIA NIH HHS, Id: R01 AG023039
  • Agency: NHLBI NIH HHS, Id: R01 HL067724
  • Agency: NHLBI NIH HHS, Id: R01 HL067724-12
  • Agency: NHLBI NIH HHS, Id: R01 HL091469
  • Agency: NHLBI NIH HHS, Id: R01 HL091469-05
  • Agency: NHLBI NIH HHS, Id: R01 HL102738
  • Agency: NHLBI NIH HHS, Id: R01 HL102738-03
  • Agency: NHLBI NIH HHS, Id: R01 HL112330
  • Agency: NHLBI NIH HHS, Id: R21 HL098802
  • Agency: NHLBI NIH HHS, Id: R21 HL098802-02

Mesh Terms

  • Animals
  • Cardiomegaly
  • Cells, Cultured
  • Constriction, Pathologic
  • Gene Expression
  • Gene Expression Regulation
  • I-kappa B Proteins
  • Mice
  • Mice, Knockout
  • Muscle Proteins
  • NF-kappa B
  • Protective Agents
  • Rats
  • SKP Cullin F-Box Protein Ligases