Elucidation of Molecular Biological Mechanisms for Angiogenic Proliferative Action of Heparin

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Last year, we evidenced and reported that angiogenic growth factors, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were produced and released from cardiac tissue, being accumulated in pericardial fluid, and that the concentrations of these growth factors in pericardial fluid from ischemic myocardium were increased, which might contribute to collateral development. This year, we studied whether VEGF and bFGF are released from the heart in response to myocardial ischemia into the pericardial space. The level of VEGF in pericardial fluid was increased only in patients with severe rest angina within 2 days before emergency CABG,while bFGF was increased in all patients undergoing CABG for coronary artery disease. We also evaluated whether HSP 70 acts as a chaperone for the release of bFGF not having the signal sequence. The levels of HSP 70 in pericardial fluid of the patients with unstable angina was twofold higher than that of those with non-ischemic heart disease. Subsequently, we examined the effect of the intramyocardial administration of bFGF combined with gelatin on the development of collateral vessels in dogs with acute coronary occlusion. The dogs treated with control-released bFGF had well-developed collaterals compared with placebo-treated dogs. We concluded that the local sustained delivery of angiogenic growth factors successfully accelerated and potentiated the development of collateral vessels.