title: Transgenic over expression of ectonucleotide triphosphate diphosphohydrolase-1 protects against murine myocardial ischemic injury.
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.
authors.affiliation: Division of Cardiovascular Medicine and Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Cai
authors.forename: Zachary M
authors.initials: ZM
authors.lastname: Huttinger
authors.forename: Heng
authors.initials: H
authors.lastname: He
authors.forename: Weizhi
authors.initials: W
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Goodman
authors.forename: Debra G
authors.initials: DG
authors.lastname: Wheeler
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Druhan
authors.forename: Jay L
authors.initials: JL
authors.lastname: Zweier
authors.forename: Karen M
authors.initials: KM
authors.lastname: Dwyer
authors.forename: Guanglong
authors.initials: G
authors.lastname: He
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; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism*; D001081:Apyrase / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000235:genetics*; D010766:Phosphorylation; D043704:Receptor, Adenosine A2B / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D015703:Antigens, CD; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D043704:Receptor, Adenosine A2B; D001081:Apyrase; C067869:CD39 antigen