title: Intramyocardial infusion of FGF-1 mimics ischemic preconditioning in pig myocardium.
abstract: Previous studies on the mRNA and protein level suggested a cardioprotective role of FGF-1. These presumed actions of FGF-1 and FGF-2, as well as the underlying mechanisms, were investigated in this study. Human recombinant FGF-1 (0.5 microgram/ml, 20 microliters/min) and FGF-2 (2 micrograms/ml) were applied by means of direct intramyocardial infusion (IM) for 60 min prior to a 60 min LAD-occlusion and 120 min reperfusion. Myocardial infarction compared to the region at risk was significantly decreased by FGF-1 and FGF-2 treatment (FGF-1: 51.8 +/- 7.7%, respectively. FGF-2: 57.3 +/- 6.5% v control 83.4 +/- 2.8%, P < 0.05). The increase in survival time was about 33 min, and equalled that of ischemic preconditioning. This effect was caused by the mitogenic part of the molecule, since infusion of a truncated version of FGF-1 (0.5-1 microgram/ml), lacking mitogenicity but maintaining hemodynamic activity, did not induce cardioprotection (78.3 +/- 0.73% v control 83.4 +/- 2.8%). Suramin (0.5 microgram/ml) prevented the observed cardioprotection (77.0 +/- 1.2% v control 83.4 +/- 2.8%) proving that the cardioprotective effect is receptor-mediated. Genistein (0.5 microgram/ml), an inhibitor of tyrosine kinases, abolished the cardioprotection as well (77.2 +/- 2.4% v control: 83.4 +/- 2.8%). Immunohistochemical staining revealed an uptake and translocation of exogenous FGF-1 to a (peri-)nuclear localization in myocytes and into non-myocytes for FGF-2. We conclude that both FGF-1 and FGF-2 are cardioprotective (FGF-1 being more active on a molar basis), and mimic ischemic preconditioning. Their actions are receptor-mediated and receptor activation is involved. Uptake and transport to a (peri-)nuclear localization, seems to be a pathway of minor relevance, since it could not be blocked by tyrosine kinase receptor inhibition. Tyrosine kinase-coupled receptor occupation in general is not protective as demonstrated by the lack of effect with VEGF-infusion.
authors.affiliation: Max-Planck-Institute for Physiological and Clinical Research, W.G. Kerckhoff-Institute, Department of Experimental Cardiology, Bad Nauheim, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Htun
authors.forename: W D
authors.initials: WD
authors.lastname: Ito
authors.forename: I E
authors.initials: IE
authors.lastname: Hoefer
authors.forename: J
authors.initials: J
authors.lastname: Schaper
authors.forename: W
authors.initials: W
authors.lastname: Schaper
mesh_terms: D000818:Animals; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006439:Hemodynamics; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008432:Mathematical Computing; D008856:Microscopy, Fluorescence; D009203:Myocardial Infarction / Q000473:pathology; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D013552:Swine
chemical_list: D016222:Fibroblast Growth Factor 2; D005346:Fibroblast Growth Factors