• Paul J Schaeffer, Adam R Wende, Carolyn J Magee, Joel R Neilson, Teresa C Leone, Feng Chen, and Daniel P Kelly.
• Center for Cardiovascular Research and Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
• J. Biol. Chem. 2004 Sep 17; 279 (38): 39593-603.

AbstractTo learn more about the targets of Cn (Cn) and calcium/calmodulin-dependent protein kinase in cardiac muscle, we investigated their actions in cultured cardiac myocytes and the hearts of mice in vivo. Adenoviral-mediated expression of constitutively active forms of either pathway induced expression of peroxisome proliferator-activated receptor gamma coactivator 1alpha, a transcriptional coactivator involved in the control of multiple cellular energy metabolic pathways in cardiac myocytes. Transcriptional profiling studies demonstrated that Cn and calcium/calmodulin-dependent protein kinase activate distinct but overlapping metabolic gene regulatory programs. Expression of the nuclear receptor, peroxisome proliferator-activated receptor alpha, was markedly increased by Cn, but not calcium/calmodulin-dependent protein kinase, providing one mechanism whereby cellular fatty acid utilization genes are selectively activated by Cn. Transfection experiments demonstrated that Cn directly activates the mouse peroxisome proliferator-activated receptor alpha gene promoter. Co-transfection "add-back" experiments demonstrated that the transcription factors, myocyte enhancer factors 2C or 2D, were sufficient to confer Cn-mediated activation of the peroxisome proliferator-activated receptor alpha gene. Cn was also shown to directly activate a known peroxisome proliferator-activated receptor alpha target, muscle-type carnitine palmitoyltransferase I, providing a second mechanism by which Cn activates genes of cellular fatty acid utilization. Lastly, the gene expression of peroxisome proliferator-activated receptor gamma coactivator 1alpha and peroxisome proliferator-activated receptor alpha was reduced in the hearts of mice with cardiac-specific ablation of the Cn regulatory subunit. These data support a role for calcium-triggered signaling pathways in the regulation of cardiac energetics and identify pathway-specific control of metabolic targets.

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