Abstract 624: Ecto-enzymatic Suppression Of Atherogenesis By CD39
Platelet activation and reactivity are primarily regulated by the cell surface enzyme CD39. This ecto-apyrase maintains vascular homeostasis by catalyzing the breakdown of the potent platelet simulator ADP to yield AMP. Recent work has demonstrated a critical role for platelet activation in atherogenesis through the tethering of leukocytes and the release of chemokines. Thus we hypothesize that CD39, by metabolizing purine nucleotides released in the blood, dissipates pro-inflammatory as well as pro-thrombotic stimuli which would otherwise exacerbate atherogenesis. To examine this, cd39−/−, cd39+/− and cd39+/+ mice on the apoE−/− background were fed a high fat diet for twenty weeks. Preliminary data with limited numbers of animals previously showed increased cross-sectional plaque in cd39−/− apoE−/− double-knockout animals compared to control apoE−/− . In the current work we found that en face preparations demonstrated only a slight increase in total plaque burden (quantified as the ratio of plaque area to vessel surface area) when comparing cd39−/− apoE−/− mice to apoE−/− controls (16% ± 5 vs. 12% ± 2, n=8, p<0.05). The basis for the similar plaque burdens was presumed to be due to a paradoxical 91% decrease in platelet reactivity seen in cd39−/−apoE−/− mice compared with apoE−/− controls during whole blood aggregometry. Interestingly, cd39+− apoE−/− mice had only a 54% desensitization of their platelets, and when fed a high fat diet, had a 2-fold increase in total plaque burden compared to apoE−/− mice (25% ± 5 vs. 12% ± 2, n=6, p<0.05). Further, in both cd39−/− apoE−/− and cd39+/−apoE−/− the plaque distribution was altered from apoE−/− control animals. Cd39 deficient mice consistently had plaque in the peritoneal aorta (cd39−/−apoE−/− 18.9 ± 6.4%, cd39+/−apoE−/− 30.5 ± 3.4%, apoE−/− 10.1 ± 2.4%, p<0.03), whereas double-knockouts had limited plaque in the lesser curvature (cd39−/− apoE−/− 11 ± 2%, cd39+/− apoE−/− 25 ± 6%, apoE−/− 18 ± 3%). Percent body fat via DEXA scanning, blood pressure readings, and fasting cholesterol levels showed no significant differences across genotypes. These data reveal a new paradigm, whereby extracellular nucleotide metabolism plays a critical role in the genesis and possibly localization of atherosclerotic plaques.