Transgenic over expression of ectonucleotide triphosphate diphosphohydrolase-1 protects against murine myocardial ischemic injury

Ming Cai, Zachary M. Huttinger, Heng He, Weizhi Zhang, Feng Li, Lauren A. Goodman, Debra G. Wheeler, Lawrence J. Druhan, Jay L. Zweier, Karen M. Dwyer, Guanglong He, Anthony J.F. d'Apice, Simon C. Robson, Peter J. Cowan, Richard J. Gumina

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Modulation of purinergic signaling is critical to myocardial homeostasis. Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD-1; CD39) which converts the proinflammatory molecules ATP or ADP to AMP is a key regulator of purinergic modulation. However, the salutary effects of transgenic over expression of ENTPD-1 on myocardial response to ischemic injury have not been tested to date. Therefore we hypothesized that ENTPD-1 over expression affords myocardial protection from ischemia-reperfusion injury via specific cell signaling pathways. ENTPD-1 transgenic mice, which over express human ENTPDase-1, and wild-type (WT) littermates were subjected to either ex vivo or in vivo ischemia-reperfusion injury. Infarct size, inflammatory cell infiltrate and intracellular signaling molecule activation were evaluated. Infarct size was significantly reduced in ENTPD-1 versus WT hearts in both ex vivo and in vivo studies. Following ischemia-reperfusion injury, ENTPD-1 cardiac tissues demonstrated an increase in the phosphorylation of the cellular signaling molecule extracellular signal-regulated kinases 1/2 (ERK 1/2) and glycogen synthase kinase-3β (GSK-3β). Resistance to myocardial injury was abrogated by treatment with a non-selective adenosine receptor antagonist, 8-SPT or the more selective A 2B adenosine receptor antagonist, MRS 1754, but not the A 1 selective antagonists, DPCPX. Additionally, treatment with the ERK 1/2 inhibitor PD98059 or the mitochondrial permeability transition pore opener, atractyloside, abrogated the cardiac protection provided by ENTPDase-1 expression. These results suggest that transgenic ENTPDase-1 expression preferentially conveys myocardial protection from ischemic injury via adenosine A 2B receptor engagement and associated phosphorylation of the cellular protective signaling molecules, Akt, ERK 1/2 and GSK-3β that prevents detrimental opening of the mitochondrial permeability transition pore.

Original languageEnglish (US)
Pages (from-to)927-935
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume51
Issue number6
DOIs
StatePublished - Dec 2011

Keywords

  • Adenosine receptor
  • CD39
  • ERK 1/2
  • Ectonucleoside triphosphate diphosphohydrolase 1
  • GSK-3β
  • Myocardial ischemia
  • Reperfusion

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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