Abstract 226: Long-Term Protection Against Myocardial Infarction Provided by rAAV-Mediated Endothelial Nitric Oxide Synthase Gene Therapy
The early trigger effect of NO derived from endothelial NO synthase (eNOS) in limiting myocardial ischemic injury is well established. Previous studies have showed that eNOS gene therapy protects against myocardial infarction for 3 days. However, the long-term effect of eNOS gene therapy on myocardial ischemic injury is unknown. While Ad5 vectors result in transient gene expression, a novel recombinant adeno-associated viral vector (rAAV) enables long-lasting transgene expression in vivo due to lack of inflammation. Thus, the aim of present study was to determine the long-term effect of rAAV-mediated eNOS gene transfer on infarct size in mice. To this end, we created a rAAV vector carrying eNOS gene (rAAV/eNOS). Mice received injections in LV anterior wall of rAAV/LacZ (LacZ group) or rAAV/eNOS (eNOS group); 3 months later, they were subjected to a 30-min coronary occlusion [O] followed by 4 h reperfusion [R]. rAAV-mediated eNOS expression in myocardium was confirmed by eNOS immunohistochemistry (Fig⇓). Infarct size (% of risk region) was markedly reduced by eNOS gene therapy (18±3% vs. 43±4% in LacZ group; Fig⇓). The infarct-sparing effects of long-term eNOS gene therapy were as powerful as those observed 24 h after ischemic PC (six 4-min O/4-min R cycles) (Fig⇓). We conclude that rAAV-mediated eNOS gene therapy affords effective cardioprotection for at least 3 months, demonstrating that NO derived from eNOS not only services as a trigger to initiate the procedure of late PC but also is indeed beneficial to long-term myocardial protection and thus supporting a novel therapeutic strategy for achieving long-term prophylactic cardioprotection in patients with heart ischemic diseases.