CalDAG-GEFI Deficiency Reduces Atherosclerotic Lesion Development in Mice

Objective—Platelets are important for the development and progression of atherosclerotic lesions. However, relatively little is known about the contribution of platelet signaling to this pathological process. Our recent work identified 2 independent, yet synergistic, signaling pathways that lead to the activation of the small GTPase Rap1; one mediated by the guanine nucleotide exchange factor, CalDAG-GEFI (CDGI), the other by P2Y12, a platelet receptor for adenosine diphosphate and the target of antiplatelet drugs. In this study, we evaluated lesion formation in atherosclerosis-prone low-density lipoprotein receptor deficient (Ldlr−/−) mice lacking CDGI or P2Y12 in hematopoietic cells. Approach and Results—Lethally irradiated Ldlr−/− mice were reconstituted with bone marrow from wild-type (WT), Caldaggef1−/− (cdgI−/−), p2y12−/−, or cdgI−/−p2y12−/− (double knockout [DKO]) mice and fed a high-fat diet for 12 weeks. Ldlr−/− chimeras deficient for CDGI or P2Y12 developed significantly smaller atherosclerotic ...