title: p38 mitogen-activated protein kinase activates peroxisome proliferator-activated receptor alpha: a potential role in the cardiac metabolic stress response.
abstract: 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 (PPARalpha). Evidence has emerged that PPARalpha 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 PPARalpha 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 NH(2)-terminal A/B domain of the protein. Transient transfection studies in cardiac myocytes and in CV-1 cells utilizing homologous and heterologous PPARalpha target element reporters and mammalian one-hybrid transcription assays revealed that p38 MAPK phosphorylation of PPARalpha significantly enhanced ligand-dependent transactivation. Cotransfection studies performed with several known coactivators of PPARalpha 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 PPARalpha as a downstream effector of p38 kinase-dependent stress-activated signaling in the heart, linking extracellular stressors to alterations in energy metabolic gene expression.
authors.affiliation: Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Barger
authors.forename: A C
authors.initials: AC
authors.lastname: Browning
authors.forename: A N
authors.initials: AN
authors.lastname: Garner
authors.forename: D P
authors.initials: DP
authors.lastname: Kelly
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites; D002460:Cell Line; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D019281:Dimerization; D004789:Enzyme Activation; D007093:Imidazoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D009206:Myocardium / Q000166:cytology; D019301:Oleic Acid / Q000494:pharmacology; D010710:Phosphates / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D020798:Two-Hybrid System Techniques; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D007093:Imidazoles; D010710:Phosphates; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D019301:Oleic Acid; D012694:Serine; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole