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

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 aMHC-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.

Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-γ coactivator 1α

“…As mentioned above, the expression of PGC-1␣ and many of its target genes is repressed in various rodent models of cardiac failure (28)(29)(30)(31)(32)(33)(34)(35)(36). Consistent with these findings, PGC-1␣ was repressed by Ϸ30-40% in WT mice subjected to TAC, compared with WT controls (Fig.…”

“…A growing literature indicates that PGC-1␣ expression is altered in experimental models of heart disease (28)(29)(30)(31)(32)(33)(34)(35)(36). For example, PGC-1␣ and mitochondrial genes that are regulated by PGC-1␣ are repressed in rodent models of cardiac hypertrophy (30,31,37).…”

The breast cell growth inhibitor, estrogen down regulated gene 1, modulates a novel functional interaction between estrogen receptor alpha and transcriptional elongation factor cyclin T1

“…While we observe inhibition by EDG1 of transcriptional activity of other nuclear receptors, we did not see inhibition of the VP16 transcriptional activator (data not shown). Conversely, DNA microarray analyses of hearts from cyclin T1 transgenic mice indicate selective increases in subsets of genes, rather than a global increase in mRNA expression, when compared to nontransgenic mice (Sano et al, 2004). That transcriptional inhibition by EDG1 extends beyond the ERa does not diminish our findings; our studies suggest for the first time that ERa-mediated gene expression involves a complex interplay between the ERa, EDG1 and the transcriptional elongation machinery, with EDG1 modulating a novel functional interaction between ERa and cyclin T1.…”

Regulation of Ca2+ signalling and Ca2+-mediated cell death by the transcriptional coactivator PGC-1α

“…Along these lines, two recent important observation identified PGC-1a also as a regulator of cell death: the loss of the protein led to loss of striatal function in the brain 18 and its downregulation was shown to be responsible for apoptosis of cardiac myocytes. 20 A likely mechanism for this protection could be the known upregulation of UCPs by PGC-1a, and the consequent downregulation of mitochondrial ROS production, however, no direct experimental evidence supports such a role of PGC1a in the above pathological models.…”

“…18 Similarly, downregulation of PGC-1a in hypertrophic cardiac failure is responsible for apoptotic cell death of cardiac myocytes. 19,20 These effects might due to impaired mitochondrial function, and imply a strong antiapoptotic effect of the protein. However, the mechanisms linking PGC-1a-induced mitochondrial changes to decreased susceptibility to cell death are unknown.…”