The protein kinase C pathway mediates cardioprotection induced by cardiac-specific overexpression of fibroblast growth factor-2

Stacey L. House,¹ Susan J. Melhorn,¹ Gilbert Newman,¹ Thomas Doetschman,² , and Jo El J. Schultz¹

Departments of ¹Pharmacology and Cell Biophysics and ²Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio

Abstract: Elucidation of protective mechanisms against ischemia-reperfusion injury is vital to the advancement of therapeutics for ischemic heart disease. Our laboratory has previously shown that cardiac-specific overexpression of fibroblast growth factor-2 (FGF2) results in increased recovery of contractile function and decreased infarct size following ischemia-reperfusion injury and has established a role for the mitogen-activated protein kinase (MAPK) signaling cascade in the cardioprotective effect of FGF2. We now show an additional role for the protein kinase C (PKC) signaling cascade in the mediation of FGF2-induced cardioprotection. Overexpression of FGF2 (FGF2 Tg) in the heart resulted in decreased translocation of PKC- but had no effect on PKC-, -, or -. In addition, multiple alterations in PKC isoform translocation occur during ischemia-reperfusion injury in FGF2 Tg hearts as assessed by Western blot analysis and confocal immunofluorescent microscopy. Treatment of FGF2 Tg and nontransgenic (NTg) hearts with the PKC inhibitor bisindolylmaleimide (1 µmol/l) revealed the necessity of PKC signaling for FGF2-induced reduction of contractile dysfunction and myocardial infarct size following ischemia-reperfusion injury. Western blot analysis of FGF2 Tg and NTg hearts subjected to ischemia-reperfusion injury in the presence of a PKC pathway inhibitor (bisindolylmaleimide, 1 µmol/l), an mitogen/extracellular signal-regulated kinase/extracellular signal-regulated kinase (MEK/ERK) pathway inhibitor (U-0126, 2.5 µmol/l), or a p38 pathway inhibitor (SB-203580, 2 µmol/l) revealed a complicated signaling network between the PKC and MAPK signaling cascades that may participate in FGF2-induced cardioprotection. Together, these data suggest that FGF2-induced cardioprotection is mediated via a PKC-dependent pathway and that the PKC and MAPK signaling cascades are integrally connected downstream of FGF2.

Key Words: ischemia-reperfusion injury • cardiac dysfunction • myocardial infarction • kinase signaling cross talk

Address for reprint requests and other correspondence: J. J. Schultz, Dept. of Pharmacology and Cell Biophysics, Univ. of Cincinnati, College of Medicine, 231 Albert Sabin Way, ML 0575, Cincinnati, OH 45267 (e-mail: schuljo{at}email.uc.edu)

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