Intramyocardial Infusion of FGF-1 Mimics Ischemic Preconditioning in Pig Myocardium

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 (0.5μg/ml, 20μl/min) and FGF-2 (2μg/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%vcontrol 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 (0.5–1μg/ml), lacking mitogenicity but maintaining hemodynamic activity, did not induce cardioprotection (78.3±0.73%vcontrol 83.4±2.8%). Suramin (0.5μg/ml) prevented the observed cardioprotection (77.0±1.2%vcontrol 83.4±2.8%) proving that the cardioprotective effect is receptor-mediated. Genistein (0.5μg/ml), an inhibitor of tyrosine kinases, abolished the cardioprotection as well (77.2±2.4%vcontrol: 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.