Published Online
on December 1, 2003

A more recent version of this article appeared on December 23, 2003

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Submitted on June 18, 2003
Revised on August 15, 2003
Accepted on August 19, 2003

Cardiac-Specific Overexpression of Fibroblast Growth Factor-2 Protects Against Myocardial Dysfunction and Infarction in a Murine Model of Low-Flow Ischemia

Stacey L. House BS, Craig Bolte BA, Ming Zhou MD, PhD, Thomas Doetschman PhD, Raisa Klevitsky MD, Gilbert Newman BS, and Jo El J. Schultz PhD^*

From the Departments of Pharmacology and Cell Biophysics, Molecular Genetics, Biochemistry, and Microbiology (M.Z., T.D.), University of Cincinnati, Ohio.

^* To whom correspondence should be addressed. E-mail: schuljo{at}email.uc.edu.

Background--Preconditioning the heart before an ischemic insult has been shown to protect against contractile dysfunction, arrhythmias, and infarction. Pharmacological studies have suggested that fibroblast growth factor-2 (FGF2) is involved in cardioprotection. However, because of the number of FGFs expressed in the heart and the promiscuity of FGF ligand-receptor interactions, the specific role of FGF2 during ischemia-reperfusion injury remains unclear.

Methods and Results--FGF2-deficient (Fgf2 knockout) mice and mice with a cardiac-specific overexpression of all 4 isoforms of human FGF2 (FGF2 transgenic [Tg]) were compared with wild-type mice to test whether endogenous FGF2 elicits cardioprotection. An ex vivo work-performing heart model of ischemia was developed in which murine hearts were subjected to 60 minutes of low-flow ischemia and 120 minutes of reperfusion. Preischemic contractile function was similar among the 3 groups. After ischemia-reperfusion, contractile function of Fgf2 knockout hearts recovered to 27% of its baseline value compared with a 63% recovery in wild-type hearts (P<0.05). In FGF2 Tg hearts, an 88% recovery of postischemic function occurred (P<0.05). Myocardial infarct size was also reduced in FGF2 Tg hearts compared with wild-type hearts (13% versus 30%, P<0.05). There was a 2-fold increase in FGF2 release from Tg hearts compared with wild-type hearts (P<0.05). No significant alterations in coronary flow or capillary density were detected in any of the groups, implying that the protective effect of FGF2 is not mediated by coronary perfusion changes.

Conclusions--These results provide evidence that endogenous FGF2 plays a significant role in the cardioprotective effect against ischemia-reperfusion injury.

Key words: ischemia • myocardial infarction • myocardial stunning • growth substances

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