The applicant hypothesizes that reactive oxygen species are a major cause of injury in cardiac ischemic tissue following reperfusion and that the functional recovery of the aging heart will be improved by overexpressing one or more of the antioxidant enzymes. The applicant indicates that this hypothesis is supported by previous observations that exogenous addition of various antioxidant enzymes, such as SOD and catalase, provide protection to the heart against ischemia/reperfusion injury. However, the effectiveness of the enzyme therapy is not understood because these enzymes cannot penetrate the cardiac cells where the free radicals are produced. In order to identify the rate limiting antioxidant enzyme, mice carrying a SOD or catalase transgene at the sense configuration will be generated. These transgenes are being designed to be under the control of human b-actin promoter to insure high levels of transcription in the hearts of animals. Since SOD and catalase work in concert to remove oxygen free radicals, mice containing a combination of two transgenes will also be obtained by breeding two transgenic founder mice each bearing a different transgene. Expression of these transgenes in the hearts of control and transgenic mice at three ages (3, 10, and 24 month-old) will be examined at enzyme activity levels along with other antioxidant enzymes. Correlations between the altered levels of myocardial antioxidant enzymes and susceptibility to ischemia/ reperfusion injury will be defined by both physiological and biochemical analyses using the mouse heart perfusion model developed in the applicant's laboratory.
