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

Motoaki Sano, Sam C. Wang, Manabu Shirai, Fernando Scaglia, Min Xie, Satoshi Sakai, Toru Tanaka, Prathit A. Kulkarni, Philip M. Barger, Keith A. Youker, George E. Taffet, Yasuo Hamamori, Lloyd H. Michael, William J. Craigen, Michael D. Schneider

Research output: Contribution to journalArticle

125 Scopus citations

Abstract

Hypertrophy allows the heart to adapt to workload but culminates in later pump failure; how it is achieved remains uncertain. Previously, we showed that hypertrophy is accompanied by activation of cyclin T/Cdk9, which phosphorylates the C-terminal domain of the large subunit of RNA polymerase II, stimulating transcription elongation and pre-mRNA processing; Cdk9 activity was required for hypertrophy in culture, whereas heart-specific activation of Cdk9 by cyclin T1 provoked hypertrophy in mice. Here, we report that αMHC-cyclin T1 mice appear normal at baseline yet suffer fulminant apoptotic cardiomyopathy when challenged by mechanical stress or signaling by the G-protein Gq. At pathophysiological levels, Cdk9 activity suppresses many genes for mitochondrial proteins including master regulators of mitochondrial function (peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1), nuclear respiratory factor-1). In culture, cyclin T1/Cdk9 suppresses PGC-1, decreases mitochondrial membrane potential, and sensitizes cardiomyocytes to apoptosis, effects rescued by exogenous PGC-1. Cyclin T1/Cdk9 inhibits PGC-1 promoter activity and preinitiation complex assembly. Thus, chronic activation of Cdk9 causes not only cardiomyocyte enlargement but also defective mitochondrial function, via diminished PGC-1 transcription, and a resulting susceptibility to apoptotic cardiomyopathy.

Original languageEnglish
Pages (from-to)3559-3569
Number of pages11
JournalEMBO Journal
Volume23
Issue number17
DOIs
StatePublished - Sep 1 2004
Externally publishedYes

Keywords

  • Cardiac
  • Cyclin T
  • Cyclin-dependent kinase-9
  • Heart failure
  • Mitochondria

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    Sano, M., Wang, S. C., Shirai, M., Scaglia, F., Xie, M., Sakai, S., Tanaka, T., Kulkarni, P. A., Barger, P. M., Youker, K. A., Taffet, G. E., Hamamori, Y., Michael, L. H., Craigen, W. J., & Schneider, M. D. (2004). Activation of cardiac Cdk9 represses PGC-1 and confers a predisposition to heart failure. EMBO Journal, 23(17), 3559-3569. https://doi.org/10.1038/sj.emboj.7600351