Transgenic swine: Expression of human CD39 protects against myocardial injury

Wheeler, Debra G.; Joseph, Matthew E.; Mahamud, Shouvik D.; Aurand, William L.; Mohler, Peter J.; Pompili, Vincent J.; Dwyer, Karen M.; Nottle, Mark B.; Harrison, Sharon J.; d'Apice, Anthony J.F.; Robson, Simon C.; Cowan, Peter J.; Gumina, Richard J.

doi:10.1016/j.yjmcc.2012.01.002

« Previous Next »Journal of Molecular and Cellular Cardiology
Volume 52, Issue 5 , Pages 958-961, May 2012

Transgenic swine: Expression of human CD39 protects against myocardial injury☆

Debra G. Wheeler
- Division of Cardiovascular Medicine, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
Matthew E. Joseph
- Division of Cardiovascular Medicine, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
Shouvik D. Mahamud
- Division of Cardiovascular Medicine, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
William L. Aurand
- Division of Cardiovascular Medicine, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
Peter J. Mohler
- Division of Cardiovascular Medicine, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
- Department of Cell Biology and Physiology, The Ohio State University, Columbus, OH, USA
Vincent J. Pompili
- Division of Cardiovascular Medicine, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
Karen M. Dwyer
- Immunology Research Centre, St. Vincent's Hospital, Melbourne, Victoria, Australia
- Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
Mark B. Nottle
- Department of Obstetrics and Gynecology, University of Adelaide, Adelaide, Australia
Sharon J. Harrison
- Department of Obstetrics and Gynecology, University of Adelaide, Adelaide, Australia
Anthony J.F. d'Apice
- Immunology Research Centre, St. Vincent's Hospital, Melbourne, Victoria, Australia
- Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
Simon C. Robson
- Transplant Institute, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Peter J. Cowan
- Immunology Research Centre, St. Vincent's Hospital, Melbourne, Victoria, Australia
- Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
Richard J. Gumina
- Division of Cardiovascular Medicine, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA
- Department of Cell Biology and Physiology, The Ohio State University, Columbus, OH, USA
- Corresponding author at: Interventional Cardiovascular Research, Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University, Davis Heart & Lung Research Institute, Suite 200, 473 W. 12th Avenue, Columbus, OH 43210-1252, USA. Tel.: +1 614 293 4967(office); fax: +1 614 293 5614.

Received 18 December 2011; accepted 3 January 2012. published online 16 January 2012.

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 60min followed by 3hours 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. Control: 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.

Abbreviations: ADP, adenosine diphosphate, AMP, adenosine monophosphate, ATP, adenosine triphosphate, MI, myocardial infarction, ENTPD-1, CD39: ectonucleoside triphosphate diphosphohydrolase 1, CD73, ecto-5′-nucleotidase, I/R, ischemia/reperfusion, LAD, left anterior descending, TTC, triphenyl tetrazolium chloride, RPP, rate-pressure product, WBC, white blood cells, FACS, fluorescence activated cell sorter