In vivo gene delivery of XIAP protects against myocardial apoptosis and infarction following ischemia/reperfusion in conscious rabbits

Abstract

Aims-We tested the hypothesis that an in vivo gene delivery of the pro-survival protein XIAP (X-chromosome linked inhibitor of apoptosis protein) protects against myocardial apoptosis and infarction following ischemia/reperfusion.Main Methods-Nineteen rabbits were chronically instrumented with an hydraulic occluder placed around the circumflex coronary artery. Adenovirus harboring XIAP (Ad.XIAP; 1×10 10 pfu/ml) or β-galactosidase (5×10 9 pfu/ml), as a control, was constructed and transfected into the heart using a catheter place into the left ventricle accompanied by cross-clamping. 1-2 weeks after gene delivery, myocardial ischemia was induced by a 30-min occlusion followed by reperfusion for four days. Protein expression was determined by Western blot and Apoptosis (% of myocytes) was quantified by TUNEL staining.Key Findings-Myocardial infarct size, expressed as a fraction of the area at risk, was reduced in Ad.XIAP (n=5) compared to control (n=7) rabbits (21±3% vs. 30±2%, p<0.05). Apoptosis was reduced in Ad.XIAP rabbits compared to control rabbits (2.96±0.68% vs. 8.98±1.84%, p<0.01). This was associated with an approximate 60% decrease in the cleaved caspase-3 level in Ad.XIAP rabbits compared to control rabbits.Significances-The current findings demonstrate that overexpression of XIAP via in vivo delivery in an adenovirus can reduce both myocardial apoptosis and infarction following ischemia/ reperfusion, at least in part, due to the ability of XIAP to inhibit caspase-3. These findings confirm previous work suggesting a link between myocardial apoptosis and infarction i.e., anti-apoptotic therapy was effective in reducing myocardial infarct size.

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