The cardioprotective effect of the low molecular weight isoform of fibroblast growth factor-2: The role of JNK signaling

Siyun Liao, Darius Porter, Alana Scott, Gilbert Newman, Thomas C Doetschman, Jo El J Schultz

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Our laboratory showed that overexpression of fibroblast growth factor-2 (FGF2) protected the heart against ischemia-reperfusion injury. FGF2 has different protein isoforms (low [LMW] and high [HMW] molecular weight isoforms) produced from alternative translation start sites. However, which FGF2 isoform(s) mediates this cardioprotection, and which signaling pathway (i.e., mitogen-activated protein kinase (MAPK)) elicits FGF2 isoform-induced cardioprotection remains to be elucidated. Methods and results: Wildtype, Fgf2 KO (absence of all FGF2 isoforms) and FGF2 LMWKO (absence of LMW isoform) hearts were subjected to an ex vivo work-performing heart ischemic model of 60 min ischemia and 120 min reperfusion. There was a significant decrease in the recovery of post-ischemic contractile function (p < 0.05) in Fgf2 KO and FGF2 LMWKO mouse hearts compared to wildtype hearts. Following ischemia-reperfusion injury, MKK4/7, JNK, and c-Jun were significantly phosphorylated (i.e., activated), and the levels of TUNEL-positive nuclei and caspase 3 cleavage were significantly increased in vehicle-treated Fgf2 KO and FGF2 LMWKO compared to wildtype hearts (p < 0.05). A novel JNK pathway inhibitor, CEP11004 (50 nM), significantly restored the post-ischemic contractile function and reduced myocardial cell death, as measured by CK release and apoptotic markers, compared to DMSO-treated cohorts (p < 0.05). Overall, our data indicate that the LMW isoform has an important role in restoring cardiac function after ischemia-reperfusion (I/R) injury. These results provide unequivocal evidence that inhibition of JNK signaling is involved in FGF2 LMW isoform-mediated cardioprotection and that the potential mechanism may be through inhibition of the apoptotic process.

Original languageEnglish (US)
Pages (from-to)106-120
Number of pages15
JournalJournal of Molecular and Cellular Cardiology
Volume42
Issue number1
DOIs
Publication statusPublished - Jan 2007
Externally publishedYes

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Keywords

  • Apoptosis
  • Cardioprotection
  • Fibroblast growth factor
  • Genetically altered mice
  • Ischemia-reperfusion injury
  • JNK signaling
  • Low molecular weight isoform

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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