Cardiac-specific overexpression of fibroblast growth factor-2 protects against myocardial dysfunction and infarction in a murine model of low-flow ischemia.
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.


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.
House
Stacey L
SL
Department of Pharmacology and Cell Biophysics, University of Cincinnati, 231 Albert Sabin Way, ML 0575, Cincinnati, Ohio 45267, USA.
Bolte
Craig
C
Zhou
Ming
M
Doetschman
Thomas
T
Klevitsky
Raisa
R
Newman
Gilbert
G
Schultz
Jo El J
Jel J
D000818:Animals; D003326:Coronary Circulation; D019610:Cytoprotection; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006321:Heart / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism*
D016222:Fibroblast Growth Factor 2