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J. Biol. Chem., Vol. 279, Issue 38, 39593-39603, September 17, 2004

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Calcineurin and Calcium/Calmodulin-dependent Protein Kinase Activate Distinct Metabolic Gene Regulatory Programs in Cardiac Muscle^*

Paul J. Schaeffer¶, Adam R. Wende, Carolyn J. Magee, Joel R. Neilson||, Teresa C. Leone, Feng Chen, and Daniel P. Kelly**

From the Center for Cardiovascular Research and Departments of Medicine, ^**Molecular Biology & Pharmacology, and Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110 and the ^||Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305

To 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 coactivator 1, 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 , 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 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 gene. Cn was also shown to directly activate a known peroxisome proliferator-activated receptor 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 coactivator 1 and peroxisome proliferator-activated receptor 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.

Received for publication, April 1, 2004 , and in revised form, July 9, 2004.

^* This work was supported in part by National Institutes of Health Grants RO1-DK45416 (to D. P. K.) and RO1-HL58493 (to D. P. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Supported by individual National Research Service Award, Grant F32-AR48758, from NIAMS, National Institutes of Health.

To whom correspondence should be addressed: Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO 63110. Tel.: 314-362-8908; Fax: 314-362-0186; E-mail: dkelly{at}im.wustl.edu.

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