Ischemic heart disease is a major cause of death in industrialized societies. Myocardial ischemia occurs when there is an interruption of blood flow to the heart. Restoration of blood flow, termed reperfusion, is required to salvage the ischemic heart from further injury. Reperfusion itself may cause further damage exacerbating the injury induced by ischemia. Ischemia-reperfusion (I-R) injury is seen during heart attacks, and may occur in patients undergoing heart transplantation, angioplasty, coronary bypass surgery and anti-thrombolytic drug therapy. Thus interventions which increase cardiac resistance to I-R injury are of clinical interest. FGF-2 is a multifunctional protein which is present in the heart and other organs, and exerts its biological effects by binding to tyrosine kinase receptors at the cell surface. In addition to being a potent mitogen, FGF-2 appears capable of protecting differentiated neuronal cells from injury, degradation and death. In cultured cardiomyocytes, FGF-2 administration prevented cell damage induced by $\rm H\sb2O\sb2$ and serum starvation. We therefore examined whether FGF-2 would act in a cardioprotective manner in cardiac I-R injury. We have shown that FGF-2 is cardioprotective against I-R injury in a chelerythrine-inhibitable fashion, implicating PKC in the mechanism of protection. This cardioprotection induced by FGF-2 against I-R may be receptor mediated as indicated by increased levels of phosphorylated tyrosine residues upon FGF-2 administration. In addition, we have provided evidence indicating that FGF-2 administration results in translocation and presumably activation of several PKC subtypes within cardiomyocytes, in the context of the whole heart, suggesting that FGF-2 may directly increase resistance of these cells to injury in situ. This FGF-2-induced cardioprotection seems to be independent of MAPK activation and may involve the activation and/or translocation of the various PLC isoforms, $\beta$ARK1, c-fos, c-jun and src. Possible clinical applications for the cardioprotective effects of FGF-2 against I-R injury include: administration immediately after a heart attack; during restoration of blood flow to ischemic regions upon angioplasty or coronary bypass surgery; or during heart transplantation. More research into how FGF-2 protects against I-R injury may lead to an optimization of FGF-2 therapy and the utilization of endogenous FGF-2 to combat cardiomyocyte damage. (Abstract shortened by UMI.)