Gene therapy for myocardial protection - Transfection of donor hearts withheat shock protein 70 gene protects cardiac function against ischemia-reperfusion injury

Background-Heat shock protein 70 (HSP70) gene transfection has been shown t o enhance myocardial tolerance after normothermic ischemia-reperfusion. We investigated the effect of HSP70 gene transfection on mechanical and endoth elial function in a protocol mimicking clinical heart preservation. Methods and Results-Rat hearts were infused ex vivo with Hemagglutinating V irus of Japan-liposome complex containing HSP70 gene (HSP, n=8) or no gene (CON, n=8), and heterotopically transplanted into recipient rats. Four days after surgery, transfected hearts were perfused on a Langendorff apparatus for 45 minutes, arrested with St Thomas' No, 1 cardioplegia for 4 hours at 4 degreesC, and reperfused for 1 hour. Mechanical and endothelial function was studied before and after ischemia. Creatine kinase was measured in rep erfusion effluent. Hearts underwent Western blotting and immunohistochemist ry to confirm HSP70 overexpression. Postischemic recovery of mechanical fun ction (% preischemic+/-SEM) was greater in HSP versus CON: Left ventricular developed pressure recovery was 76.7+/-3.9% versus 60.5+/-3.1% (P<0.05); d P/dtmax recovery was 79.4+/-4.9% versus 56.2+/-3.2% (P<0.05); dP/dtmin reco very was 74.8+/-4.6% versus 57.3+/-3.6% (P<0.05), Creatine kinase release w as attenuated in HSP versus CON: 0.22+/-0.02 versus 0.32+/-0.04 IU/min/g we t wt. (P<0.05). Recovery of coronary flow was greater in HSP versus CON: 76 .5+/-3.8% versus 59.2+/-3.2% (P<0.05). Recovery of coronary response to 5-h ydroxytryptamine (5x10(-5) mol/L) was 55.6+/-4.7% versus 23.9+/-3.2% (P<0.0 5); recovery of coronary response to glyceryltrinitrate (15 mg/L) was not d ifferent between HSP and CON: 87.4+/-6.9% versus 84.3+/-5.8% (NS). Conclusions-In a clinically relevant donor heart preservation protocol, HSP 70 gene transfection protects both mechanical and endothelial function.