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

Stacey L. House, Susan J. Melhorn, Gilbert Newman, Thomas C Doetschman, Jo El J Schultz

Research output: Contribution to journalArticle

21 Citations (Scopus)

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-δ but had no effect on PKC-α, -ε, or -ζ. 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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume293
Issue number1
DOIs
StatePublished - Jul 2007
Externally publishedYes

Fingerprint

Fibroblast Growth Factor 2
Protein Kinase C
Reperfusion Injury
Mitogen-Activated Protein Kinases
Extracellular Signal-Regulated MAP Kinases
Western Blotting
MAP Kinase Signaling System
Protein C Inhibitor
Recovery of Function
Protein Kinase Inhibitors
Mitogens
Confocal Microscopy
Myocardial Ischemia
Protein Isoforms
Myocardial Infarction

Keywords

  • Cardiac dysfunction
  • Ischemia-reperfusion injury
  • Kinase signaling cross talk
  • Myocardial infarction

ASJC Scopus subject areas

  • Physiology

Cite this

The protein kinase C pathway mediates cardioprotection induced by cardiac-specific overexpression of fibroblast growth factor-2. / House, Stacey L.; Melhorn, Susan J.; Newman, Gilbert; Doetschman, Thomas C; Schultz, Jo El J.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 293, No. 1, 07.2007.

Research output: Contribution to journalArticle

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