Abstract 3928: Endogenous Cd39 Promotes Cardiac Rupture Following Myocardial Infarction
CD39 (NTPDase1) is the predominant ATP diphosphohydrolase (ATPDase) in vascular endothelium and the leukocyte surface. CD39 functions as a potent endogenous suppressor of thrombosis and inflammation which can protect the heart or brain from transient ischemic insult. To understand whether CD39 might play a role in cardiac remodeling following permanent occlusion of a coronary artery, we assessed its role in a murine model of frank myocardial infarction (MI). MI was induced in CD39−/− (KO) mice and CD39−/− (WT) mice by left anterior descending coronary artery ligation. The survival rate within 4 weeks after MI was significantly higher in KO mice than in WT mice (KO 100% vs WT 38%; P<0.05, n=11 for each group). Necropsy revealed the presumptive cause of death in all WT, but not KO mice, to have been cardiac rupture. To explore how CD39 might contribute to myocardial rupture, we examined the induction of matrix metalloproteinase (MMP)-2 and 9, an important matrix-degrading enzyme. MMP-9 mRNA was significantly reduced in ischemic heart tissue in KO mice (by 39.4%; P<0.001, n=4) compared with WT mice at 3 days after myocardial infarction. Moreover, zymography showed MMP-2 and MMP-9 activity were significantly decreased in ischemic myocardium from KO mice compared with WT mice (by 40% and 57%; p<0.05, n=3, respectively). Analysis of non-stimulated leukocytes from whole blood from KO and WT mice showed that the induction of MMP-9 (though not MMP-2) was significantly reduced in KO cells (by 49%; p<0.05, n=3, respectively) compared with WT cells. This represents the first work to demonstrate a role for CD39 in the degradation of myocardial matrix leading to cardiac rupture after MI, through the the induction of endogenous matrix metallproteinases. Experiments are now underway to generate tissue-specific CD39 deletional mutants to explore the unique contribution of endothelial, cardiac myocyte, and monocyte CD39 to the pathological cardiac remodeling and rupture observed following myocardial infarction.