Abstract 17942: A Novel Transgenic Pig Model Overexpressing Ectonucleoside Triphosphate Diphosphohydrolase 1 (entpd-1/cd39) Demonstrates Reduced Myocardial Injury

Abstract

Background: Ectonucleoside Triphosphate Diphosphohydrolase-1 (ENTPD-1/CD39) rapidly converts ATP and ADP to AMP which is further degraded by ecto-5’-nucleotidase (CD73) to adenosine, an anti-thrombotic, vasodilatory and cardiovascular protective mediator. The objective was to determine whether overexpression of ENTPD1 reduces myocardial ischemia-reperfusion injury in a large animal model of myocardial injury. Methods: Transgenic pigs expressing human ENTPD-1 under the control of the H-2Kb promoter were generated via somatic cell nuclear transfer. Myocardial ischemia-reperfusion (I/R) injury was evaluated in transgenic pigs overexpressing human ENTPD1 (CD39). I/R injury was induced by intracoronary balloon inflation in the left anterior descending (LAD) artery for 60 min followed by 3 hours of reperfusion. Myocardial infarct size was determined by staining with triphenyl tetrazolium chloride (TTC) and the area-at-risk was delineated by perfusion with 5% Phthalo Blue. For all assessments the operator was blinded to animal genotype. Results: Expression of ENTPD1 in the cardiac tissue was confirmed by Western analysis and immunohistochemistry. In response to 60 minutes of left anterior artery ischemia followed by 3 hours of reperfusion, ENTPD1 animals displayed a marked reduction in infarct size compared to wild-type littermate controls (WT: 44.7±5.2% vs ENTPD1: 17.2±4.3%; Figure). Conclusions: Overexpression of human ENTPD1 significantly attenuates myocardial infarction in a novel large animal transgenic model of myocardial ischemia-reperfusion injury.