The influence of FGF2 high molecular weight (HMW) isoforms in the development of cardiac ischemia-reperfusion injury

Siyun Liao, Janet R. Bodmer, Mohamad Azhar, Gilbert Newman, J. Douglas Coffin, Thomas C Doetschman, Jo El J Schultz

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13 Scopus citations

Abstract

Fibroblast growth factor 2 (FGF2) consists of multiple protein isoforms (low [LMW] and high molecular weight [HMW]), which are localized to different cellular compartments, indicating unique biological activity. We previously showed that the LMW isoform is important in protecting the heart from myocardial dysfunction associated with ischemia-reperfusion (I/R) injury, but the roles of the HMW isoforms remain unknown. To elucidate the role of HMW isoforms in I/R and cardioprotection, hearts from novel mouse models, in which the murine FGF2 HMWs are knocked out (HMWKO) or the human FGF2 24kDa HMW isoform is overexpressed (HMW Tg) and their wildtype (Wt) or non-transgenic (NTg) cohorts were subjected to an ex vivo work-performing heart model of I/R. There was a significant improvement in post-ischemic recovery of cardiac function in HMWKO hearts (76 ± 5%, p<0.05) compared to Wt hearts (55 ± 5%), with a corresponding decrease in HMW Tg function (line 20: 38 ± 6% and line 28: 33 ± 4%, p<0.05) compared to non-transgenic hearts (68 ± 9%). FGF2 LMW isoform was secreted from Wt and HMWKO hearts during I/R, and a FGF receptor (FGFR) inhibitor, PD173074 caused a decrease in cardiac function when administered in I/R in Wt and FGF2 HMWKO hearts (p<0.05), indicating that FGFR is involved in FGF2 LMW isoform's biological effect in ischemia-reperfusion injury. Moreover, overexpression of HMW isoform reduced FGFR1 phosphorylation/activation with no further decrease in the phosphorylation state in the presence of the FGFR inhibitor. Overall, our data indicate that HMW isoforms have a detrimental role in the development of post-ischemic myocardial dysfunction.

Original languageEnglish (US)
Pages (from-to)1245-1254
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume48
Issue number6
DOIs
Publication statusPublished - Jun 2010

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Keywords

  • Cardioprotection
  • Fibroblast growth factor
  • Fibroblast growth factor receptor
  • Human or mouse FGF
  • Ischemia-reperfusion injury
  • Low or high molecular weight isoforms

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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