p38 mitogen-activated protein kinase activates peroxisome proliferator-activated receptor alpha - 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 con trolled at the transcriptional level via the nuclear receptor peroxisome pr oliferator-activated receptor alpha (PPAR alpha). Evidence has emerged that PPAR alpha activity is activated as a component of an energy metabolic str ess response. The p38 mitogen-activated protein kinase (MAPK) pathway is ac tivated by cellular stressors in the heart, including ischemia, hypoxia, an d hypertrophic growth stimuli. We show here that PPAR alpha is phosphorylat ed in response to stress stimuli in rat neonatal cardiac myocytes; in vitro kinase assays demonstrated that p38 MAPK phosphorylates serine residues lo cated within the NH2-terminal A/B domain of the protein. Transient transfec tion 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 s ignificantly enhanced ligand-dependent transactivation. Cotransfection stud ies performed with several known coactivators of PPAR alpha demonstrated th at p38 MAPK markedly increased coactivation specifically by PGC-1, a transc riptional coactivator implicated in myocyte energy metabolic gene regulatio n and mitochondrial biogenesis. These results identify PPAR alpha as a down stream effector of p38 kinase-dependent stress-activated signaling in the h eart, linking extracellular stressors to alterations in energy metabolic ge ne expression.