Abstract 1608: rAAV-Mediated Cyclooxygenase-2 Gene Therapy Affords Permanent (1 year) Cardioprotection Without Adverse Functional Consequences
Although COX-2 is known to play an obligatory role in the infarct-sparing effects of late preconditioning, the long-term effects of COX-2 gene therapy on myocardial ischemic injury and function are unknown. To address this issue, we created a recombinant adeno-associated viral vector (rAAV) carrying COX-2 gene (rAAV/COX-2); because of chromosomal integration of transgene and lack of inflammation, this vector enables long-lasting transgene expression, at least 1 year. Mice received injections in LV anterior wall of rAAV/LacZ (LacZ group) or rAAV/COX-2 (COX-2 group); either 3 months or 1 year later, they were subjected to a 30-min coronary occlusion followed by 4 h of reperfusion. Cardiac COX-2 gene expression was confirmed by immunoblotting at 3 months and by immunohistochemistry at 1 year after gene transfer (Fig⇓). In COX-2 group, infarct size (% of risk region) was significantly reduced both at 3 months (20.4±3.6%, n=8, vs. 43.1±4.1%, n=6, in LacZ group) and at 1 year (21.3±5.0%, n=5, vs. 45.3±3.2%, n=7, in LacZ group, Fig⇓). The infarct-sparing effects of COX-2 gene therapy at 1 year were as powerful as those observed at 3 months. COX-2 gene transfer (n=7) had no effect on LV dimensions or function up to 1 year as compared with LacZ group (n=11) (at 1 year: LVEDD 4.2±0.1 vs. 4.2±0.2 mm; LVESD 3.0±0.1 vs. 2.9±0.2 mm; FS 29±1.7 vs. 32±2.6%; EF 57±2.0 vs. 60±2.9%) (echocardiography). Histology showed no inflammation. These data demonstrate, for the first time, that rAAV-mediated COX-2 gene transfer affords long-term (1 year), possibly permanent, cardioprotection without adverse functional consequences, providing a rationale for further preclinical testing of prophylactic gene therapy.