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- Title
Activation of cardiac Cdk9 represses PGC-1 and confers a predisposition to heart failure.
- Authors
Sano, Motoaki; Wang, Sam C.; Shirai, Manabu; Scaglia, Fernando; Min Xie; Sakai, Satoshi; Tanaka, Toru; Kulkarni, Prathit A.; Barger, Philip M.; Youker, Keith A.; Taffet, George E.; Hamamori, Yasuo; Michael, Lloyd H.; Craigen, William J.; Schneider, Michael D.
- 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 thataMHC-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.
- Subjects
HEART failure; HYPERTROPHY; RNA polymerases; MESSENGER RNA; CARDIOMYOPATHIES; APOPTOSIS
- Publication
EMBO Journal, 2004, Vol 23, Issue 17, p3559
- ISSN
0261-4189
- Publication type
Article
- DOI
10.1038/sj.emboj.7600351