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Activation of cardiac Cdk9 represses PGC-1 and confers a predisposition to heart failure

Motoaki Sano1, Sam C Wang, Manabu Shirai

  • 1Center for Cardiovascular Development, Baylor College of Medicine, Houston, TX 77030, USA.

The EMBO Journal
|August 7, 2004
PubMed

Insights

Chronic cyclin T/Cdk9 activation causes heart enlargement and mitochondrial dysfunction, leading to apoptotic cardiomyopathy. This pathway, involving suppressed PGC-1, highlights a novel mechanism in heart disease progression.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Cellular Stress Response

Background:

  • Cardiac hypertrophy is an adaptive response to increased workload but can lead to heart failure.
  • The precise molecular mechanisms driving hypertrophy and subsequent pump failure remain incompletely understood.
  • Previous work implicated cyclin T/Cdk9 in hypertrophy by enhancing transcription elongation and pre-mRNA processing.

Purpose of the Study:

  • To investigate the role of cyclin T1/Cdk9 in cardiac pathophysiology under stress.
  • To elucidate the molecular mechanisms by which cyclin T1/Cdk9 impacts mitochondrial function and cardiomyocyte survival.
  • To determine the link between Cdk9 activity, PGC-1 suppression, and the development of apoptotic cardiomyopathy.

Main Methods:

  • Generation and characterization of alphaMHC-cyclin T1 transgenic mice.
  • Assessment of cardiac function and pathology following mechanical stress or Gq signaling.
  • Analysis of gene expression, focusing on mitochondrial proteins and regulators like PGC-1 and NRF-1.
  • In vitro studies using cultured cardiomyocytes to assess mitochondrial membrane potential and apoptosis.

Main Results:

  • AlphaMHC-cyclin T1 mice exhibited normal baseline function but developed severe apoptotic cardiomyopathy upon stress.
  • Pathophysiological Cdk9 activity suppressed key mitochondrial genes, including PGC-1 and NRF-1.
  • In cultured cardiomyocytes, cyclin T1/Cdk9 reduced mitochondrial membrane potential and increased apoptosis sensitivity, effects reversed by PGC-1.
  • Cyclin T1/Cdk9 was shown to inhibit PGC-1 promoter activity and preinitiation complex assembly.

Conclusions:

  • Chronic cyclin T/Cdk9 activation induces cardiomyocyte hypertrophy and impairs mitochondrial function through PGC-1 suppression.
  • This leads to diminished mitochondrial capacity and increased susceptibility to apoptotic cardiomyopathy.
  • The findings reveal a critical role for Cdk9 in regulating mitochondrial homeostasis and cardiac cell death under stress.

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