Development of Molecular Biologic Diagnostic and Therapeutic Method of Asymptomatic Myocardial Ischemia and Unstable Angina

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1. Molecular mechanism of cardiac adaptation to hypoxia/re oxygenation : We showed that hypoxia/re oxygenation activated Src family tyrosine kinases, p2l^<TAS>, three MAPK family member kinases and their upstream as well as downstream kinases, Jak/STAT tyro sine kinases, and a transcription factor ATF-2. The signal transduction cascades activated by these stimuli were at least partly different. 2. Autocrine mechanism via certain humoral factors involved in the activation of intracellular signaling induced by hypoxia/re oxygenation : (A) We showed that the activation of intracellular signaling in cardiac myocytes induced by hypoxia was mediated by VEGF in an auto crine fashion. (B) We found that similar autocrine mechanism was involved in the activation of intracellular signaling in cardiac myocytes induced by reoxygenation, and we are now isolating and purifying the humoral factor. 3. Sensitive detection of hypoxia/re oxygenation in the heart of patients with angina pectoris and acute myocardial infarction : (A) By measuring the serum levels of VEGF in patients with acute myocardial infarction undergoing early reperfusion therapy, we demonstrated that VEGF could be a sensitive indicator of ischemic (hypoxic) state. This also strongly supported the data of 2. (A). (B) We are now isolating and purifying the humoral factor involved in the activation of intracellular signaling induced by reoxygenation, and we suppose that the serum levels of the humaral factor will be a good indicator of reperfused (reoxygenated) state in the heart of these patients. 4. Anti-cell-adhesion molecule therapy against myocardial ischemia/reperfusion injury : We demonstrated using a rat model that in vivo administration of selectin oligopeptide or anti-sialy-Lewis^x mAb significantly reduced myocardial ischemia/reperfusion injury.