p38 Mitogen-activated Protein Kinase Activates Peroxisome Proliferator-activated Receptor α

doi:10.1074/jbc.M105945200

p38 Mitogen-activated Protein Kinase Activates Peroxisome Proliferator-activated Receptor α

A POTENTIAL ROLE IN THE CARDIAC METABOLIC STRESS RESPONSE*

From the Center for Cardiovascular Research, Departments of^‡Medicine, ^§Pediatrics, and ^¶Molecular Biology & Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110

Abstract

The expression of enzymes involved in fatty acid β-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 α (PPARα). Evidence has emerged that PPARα 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 PPARα 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 PPARα target element reporters and mammalian one-hybrid transcription assays revealed that p38 MAPK phosphorylation of PPARα significantly enhanced ligand-dependent transactivation. Cotransfection studies performed with several known coactivators of PPARα 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 PPARα as a downstream effector of p38 kinase-dependent stress-activated signaling in the heart, linking extracellular stressors to alterations in energy metabolic gene expression.

Footnotes

↵* This work was supported by National Institutes of Health Grants K08 HL03808 (to P. M. B.), RO1 HL58493, P50 HL61006, P30 DK56341, and P30 DK52574.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵‖ To whom correspondence should be addressed: Center for Cardiovascular Research, Box 8086, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-8908; Fax: 314-362-0186; E-mail: dkelly@imgate.wustl.edu.
Published, JBC Papers in Press, September 27, 2001, DOI 10.1074/jbc.M105945200
Abbreviations:

FAO

fatty acid β-oxidation

PPARα

peroxisome proliferator-activated receptor α

MAPK

mitogen-activated protein kinase

SAPK

stress-activated protein kinase

PGC-1

peroxisome proliferator-activated receptor γ coactivator-1

RXR

retinoid X receptor

M-CPT I

muscle-type carnitine palmitoyltransferase I

BSA

bovine serum albumin

DMEM

Dulbecco's modified Eagle's medium

PBP

peroxisome proliferator-activated receptor-binding protein

SRC

steroid receptor coactivator

ACO

acyl-CoA oxidase

GST

glutathione S-transferase

PAGE

polyacrylamide gel electrophoresis

JNK

c-Jun NH₂-terminal kinase

AF

activating function

ERK

extracellular signal-regulated kinase

FARE-1

fatty acid response element 1

RLU

relative light unit(s)

DBD

DNA binding domain
- Received June 26, 2001.
- Revision received September 19, 2001.
The American Society for Biochemistry and Molecular Biology, Inc.