p38 mitogen-activated protein kinase activates peroxisome proliferator-activated receptor α -: A potential role in the cardiac metabolic stress response

The expression of enzymes involved in fatty acid beta -oxidation (FAO), the principal source of energy production in the adult mammalian heart, is controlled at the transcriptional level via the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR alpha). Evidence has emerged that PPAR alpha activity is activated as a component of an energy metabolic stress response. The p38 mitogen-activated protein kinase (MAPK) pathway is activated by cellular stressors in the heart, including ischemia, hypoxia, and hypertrophic growth stimuli. We show here that PPAR alpha is phosphorylated in response to stress stimuli in rat neonatal cardiac myocytes; in vitro kinase assays demonstrated that p38 MAPK phosphorylates serine residues located within the NH2-terminal A/B domain of the protein. Transient transfection studies in cardiac myocytes and in CV-1 cells utilizing homologous and heterologous PPAR alpha target element reporters and mammalian one-hybrid transcription assays revealed that p38 MAPK phosphorylation of PPAR alpha significantly enhanced ligand-dependent transactivation. Cotransfection studies performed with several known coactivators of PPAR alpha demonstrated that p38 MAPK markedly increased coactivation specifically by PGC-1, a transcriptional coactivator implicated in myocyte energy metabolic gene regulation and mitochondrial biogenesis. These results identify PPAR alpha as a downstream effector of p38 kinase-dependent stress-activated signaling in the heart, linking extracellular stressors to alterations in energy metabolic gene expression.