Acute protection of ischemic heart by FGF-2: involvement of FGF-2 receptors and protein kinase C.
We examined the effect of fibroblast growth factor (FGF)-2 on myocardial resistance to injury when administered after the onset of ischemia, in vivo and ex vivo, and the role of FGF-2 receptors and protein kinase C (PKC). FGF-2 was injected into the left ventricle of rats undergoing permanent surgical coronary occlusion leading to myocardial infarction (MI). After 24 h, FGF-2-treated hearts displayed significantly reduced injury, determined by histological staining and troponin T release, and improved developed pressure compared with untreated controls. An FGF-2 mutant with diminished affinity for the tyrosine kinase FGF-2 receptor 1 (FGFR1) was not cardioprotective. FGF-2-treated hearts retained improved function and decreased damage at 6 wk after MI. In the ex vivo heart, FGF-2 administration during reperfusion after 30-min ischemia improved functional recovery and increased relative levels of PKC subtypes alpha, epsilon, and zeta in the particulate fraction, in a chelerythrine-preventable mode; it also decreased loss of energy metabolites. We conclude that intramyocardial FGF-2 administration shortly after the onset of ischemia confers protection from acute and chronic cardiac dysfunction and damage; FGF-2 delivered during reperfusion protects from ischemia-reperfusion injury; and protection by FGF-2 requires intact binding to FGFR1 and is likely mediated by PKC.
Jiang
Zhi-Sheng
ZS
Department of Human Anatomy, Faculty of Medicine, University of Manitoba, Winnipeg, Canada R2H 2A6.
Padua
Raymond R
RR
Ju
Haisong
H
Doble
Bradley W
BW
Jin
Yan
Y
Hao
Jianming
J
Cattini
Peter A
PA
Dixon
Ian M C
IM
Kardami
Elissavet
E
D000818:Animals; D015415:Biomarkers / Q000097:blood; D003971:Diastole / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage / Q000494:pharmacology*; D006352:Heart Ventricles; D007267:Injections; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000503:physiopathology / Q000517:prevention & control*; D017202:Myocardial Ischemia / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology*; D013997:Time Factors; D020107:Troponin T / Q000097:blood
D015415:Biomarkers; D017468:Receptors, Fibroblast Growth Factor; D020107:Troponin T; D016222:Fibroblast Growth Factor 2; C496350:Fgfr1 protein, rat; C496356:Fgfr2 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D011493:Protein Kinase C