CalDAG-GEFI Deficiency Reduces Atherosclerotic Lesion Development in Mice. Issue 5 (May 2016) - Boulaftali, Yacine
Abstract : 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 lesions in the aortic sinus and in aortas when compared with the Ldlr −/− /WT controls. We also observed a significant reduction in platelet-leukocyte aggregates in blood from hypercholesterolemic Ldlr −/− /cdgI −/− and Ldlr −/− /p2y12 −/− chimeras. Consistently, fewer macrophages and neutrophils were detected in the aortic sinus of Ldlr −/− /cdgI −/− and Ldlr −/− / p2y12 −/− chimeras. Compared with controls, the plaque collagen content was significantly higher in Ldlr −/− chimeras lacking CDGI. Interestingly, no statistically significant additive effects were seen in Ldlr −/− /DKO chimeras when compared with chimeras lacking only CDGI. Conclusions—: Our findings suggest that CDGI is critical for atherosclerotic plaque development in hypercholesterolemic Ldlr −/− mice because of its contribution to platelet-leukocyte aggregate formation and leukocyte recruitment to the lesion area. Abstract : Supplemental Digital Content is available in the text.