Myocardial ischemia protection by HO-1 gene delivery

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DESCRIPTION (provided by applicant): Myocardial ischemia causes inflammatory response, reduced cardiac function and irreversible cell death. Formation of reactive oxygen species (ROS) upon reperfusion of the ischemic area augments the ischemic insult. Injured cells respond to this insult by activating heme oxygenase-1 (HO-1) enzyme, which provides cytoprotective effects. Recent evidence has shown that prior induction of HO-1 protects tissues against ischemia/reperfusion (I/R) mediated injury and prolongs tissue viability. Therefore it is possible that targeted overexpression of HO-1 under non-stressful conditions will protect against future insult and provide further understanding of HO-1?s protective mechanisms. We have recently developed an adeno-associated viral vector system to deliver human HO-1 (hHO-1) directly in the rat heart and have observed long term expression of the transgene and reduction in infarct size with a single treatment of the viral vector in a coronary artery ligation (LAD) model of ischemia/reperfusion. This proposal will test the hypothesis that intracardiac delivery of hHO-1 will result in long term transcription and translation of hHO-1, provide cytoprotective effects improve cardiac hemodynamics and reduce overall mortality in LAD model of I/R injury.