Gene transfer of the pancaspase inhibitor P35 reduces myocardial infarct size and improves cardiac function.

Myocardial infarction and subsequent reperfusion lead to the activation of apoptosis, and the final destruction of the cell. The aim of this study was to show that broad-scale inhibition of caspases, the main executioners of apoptosis, improves functional outcome after ischemia and reperfusion in an in vivo model. Twenty male Wistar rats were directly injected with an adenovirus, encoding the baculoviral protein p35. Nineteen rats served as controls, and were injected with a virus only encoding green fluorescent protein (GFP). After 3 days, 12 animals were used for Langendorff perfusion experiments, the other 27 animals were submitted to in vivo infarction. Myocardial infarction was induced by ligation of the left anterior descending artery (LAD) for 30 min, and reperfusion for 24 h. Echocardiographic and hemodynamic measurements were made 24 h after infarction. Infarct size was assessed in all animals histologically. In both, in vivo and Langendorff perfused hearts, myocardial infarct size was significantly reduced in the p35 group (for in vivo experiments: 0.11+/-0.03 vs 0.33+/-0.03 in the GFP group, p<0.01), as was the ratio of infarct size to area at risk (6 vs 17%, p<0.01). Left ventricular function was similar in both groups prior to infarction, but was significantly less compromised after infarction in the p35 group. The left ventricular systolic pressure after infarction was higher in the p35 group (107+/-5 vs 92+/-4 mmHg, p<0.05), as was the maximal rate of rise of left ventricular systolic pressure dp/dt (5,659+/-585 vs 4,634+/-256 mmHg s(-1), p<0.05). Adenoviral gene transfer of the caspase inhibitor p35 leads to a significant reduction of the myocardial infarct size after ischemia and reperfusion. Hemodynamic variables were significantly improved by treatment with p35. Cardiac restricted inhibition of apoptosis seems to be a promising approach for ameliorating the effects of ischemia and reperfusion.