CD39/ectonucleoside triphosphate diphosphohydrolase 1 provides myocardial protection during cardiac ischemia/reperfusion injury

Article

关键词: ENDOGENOUS ADENOSINE;    ECTO-5'-NUCLEOTIDASE CD73;    5'-NUCLEOTIDASE ACTIVITY;    REPERFUSION INJURY;    CD39;    ECTONUCLEOTIDASES;    RECEPTORS;    MICE;    ATP;    TRANSPLANTATION;   

DOI  :  10.1161/CIRCULATIONAHA.107.690180

来源: SCIE

【 摘 要 】

Background - Extracellular adenosine, generated from extracellular nucleotides via ectonucleotidases, binds to specific receptors and provides cardioprotection from ischemia and reperfusion. In the present study, we studied ecto-enzymatic ATP/ADP-phosphohydrolysis by select members of the ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) family during myocardial ischemia. Methods and Results - As a first step, we used a murine model of myocardial ischemia and in situ preconditioning and performed pharmacological studies with polyoxometalate 1, a potent E-NTPDase inhibitor (Na-6[H2W12O40])- Polyoxo- metalate I treatment increased infarct sizes and abolished beneficial effects of preconditioning. To define relative contributions of distinct E-NTPDases, we investigated transcriptional responses of E-NTPDases I to 3 and 8 to preconditioning. We noted robust and selective induction of E-NTPDase 1 (CD39) transcript and protein. Histological analysis of preconditioned myocardium localized CD39 induction to endothelia and myocytes. Cd39(-/-) mice exhibited larger infarct sizes with ischemia (cd39(+/+) 43.0 +/- 3.3% versus cd39(-/-) 52%+/- 1.8; P<0.05), and cardioprotection was abrogated by preconditioning (cd39(+/+) 13.3%+/- 1.5 versus cd39(-/-) 50.5%+/- 2.8; P<0.01). Heightened levels of injury after myocardial ischemia and negligible preconditioning benefits in cd39(-/-) mice were corrected by infusion of the metabolic product (AMP) or apyrase. Moreover, apyrase treatment of wild-type mice resulted in 43 +/- 4.2% infarct size reduction (P<0.01). Conclusions - Taken together, these studies reveal E-NTPDase 1 in cardioprotection and suggest apyrase in the treatment of myocardial ischemia.

【 授权许可】

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