p38 mitogen-activated protein kinase activates peroxisome proliferator-activated receptor alpha - A potential role in the cardiac metabolic stress response
Pm. Barger et al., p38 mitogen-activated protein kinase activates peroxisome proliferator-activated receptor alpha - A potential role in the cardiac metabolic stress response, J BIOL CHEM, 276(48), 2001, pp. 44495-44501
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.