Modification of ischemic injury in the heart

Ischemic heart disease is the major cause of morbidity and mortality in the western world. Myocardial ischemia can be acute and chronic. In acute ischemia revascularization is essential to salvage myocyte viability, but reoxygenation paradoxically increa ses ischemic injury. In patients this is manifest as cell death, reduced pump function, and reperfusion arrhythmias. Brief episodes of ischemia and reperfusion prior to sustained ischemia (preconditioning) profoundly protects the heart. This program aims at determining one possible underlying mechanism of action with the perspective of identifying new therapeutic agents to pharmacologically evoke the response in patients. Specifically, a role for hypoxia-inducible factor 1 alpha (HIF-1a) is explored. A HI F-1a luciferase reporter mouse will be produced for studies of the role of HIF-1a for cardioprotection. In chronic myocardial ischemia scar tissue is formed, impairing heart function, which may be one cause of heart failure. Factors increasing oxygen del ivery to tissue may potentially be therapeutic in the areas surrounding scar formation. Hypoxia-inducible factor 1a is transcription factor controlling some 30 genes involved in different aspects of increasing oxygen delivery. We will deliver plasmid DNA encoding for human HIF-1a to the ischemic mouse heart using different approaches (i.e. electroporation, liposomes, local delivery, systemic delivery) to enhance the transfection efficacy. As HIF-1a induces angiogenesis and may be procarcinogenic, general organ pathology will be carefully scrutinized.