title: Transgenic swine: expression of human CD39 protects against myocardial injury.
abstract: CD39 (ectonucleoside triphosphate diphosphohydrolase-1; ENTPD-1) rapidly hydrolyzes ATP and ADP to AMP; AMP is hydrolyzed by ecto-5'-nucleotidase (CD73) to adenosine, an anti-thrombotic and cardiovascular protective mediator. While expression of human CD39 in a murine model of myocardial ischemia/reperfusion (I/R) injury confers cardiac protection, the translational therapeutic potential of these findings requires further testing in a large animal model. To determine if transgenic expression of CD39 reduces infarct size in a swine model of myocardial ischemia/reperfusion injury, transgenic pigs expressing human CD39 (hCD39) were generated via somatic cell nuclear transfer and characterized. Expression of hC39 in cardiac tissue was confirmed by immunoblot and immunohistochemistry. Myocardial 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. The ischemic area was delineated by perfusion with 5% phthalo blue and the myocardial infarct size was determined by triphenyl tetrazolium chloride (TTC) staining. During ischemia, the rate-pressure product was significantly lower in control versus hCD39-Tg swine. Following reperfusion, compared to littermate control swine, hCD39-Tg animals displayed a significant reduction in infarct size (hCD39-Tg: 17.2 ± 4.3% vs.
  
  
  METHODS
  44.7 ± 5.2%, P=0.0025). Our findings demonstrate for the first time that the findings in transgenic mouse models translate to large animal transgenic models and validate the potential to translate CD39 into the clinical arena to attenuate human myocardial ischemia/reperfusion injury.
authors.affiliation: Division of Cardiovascular Medicine, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210-1252, USA.
authors.forename: Debra G
authors.initials: DG
authors.lastname: Wheeler
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Joseph
authors.forename: Shouvik D
authors.initials: SD
authors.lastname: Mahamud
authors.forename: William L
authors.initials: WL
authors.lastname: Aurand
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Pompili
authors.forename: Karen M
authors.initials: KM
authors.lastname: Dwyer
authors.forename: Mark B
authors.initials: MB
authors.lastname: Nottle
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Harrison
authors.forename: Anthony J F
authors.initials: AJ
authors.lastname: d'Apice
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Cowan
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gumina
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D001081:Apyrase / Q000096:biosynthesis* / Q000235:genetics; D001794:Blood Pressure; D003331:Coronary Vessels / Q000473:pathology; D006339:Heart Rate; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007511:Ischemia / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D013552:Swine / Q000235:genetics*
chemical_list: D015703:Antigens, CD; D011994:Recombinant Proteins; D001081:Apyrase; C067869:CD39 antigen