| First Author | Schaeffer PJ | Year | 2004 |
| Journal | J Biol Chem | Volume | 279 |
| Issue | 38 | Pages | 39593-603 |
| PubMed ID | 15262994 | Mgi Jnum | J:93357 |
| Mgi Id | MGI:3056889 | Doi | 10.1074/jbc.M403649200 |
| Citation | Schaeffer PJ, et al. (2004) Calcineurin and calcium/calmodulin-dependent protein kinase activate distinct metabolic gene regulatory programs in cardiac muscle. J Biol Chem 279(38):39593-603 |
| abstractText | 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 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. |
