title: CalDAG-GEFI Deficiency Reduces Atherosclerotic Lesion Development in Mice.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: From the McAllister Heart Institute and Department of Medicine (Y.B., A.P.O., A.B., R.P., C.C., R.H.L., D.S.P., N.M., W.B.), Department of Biochemistry and Biophysics (W.B.), University of North Carolina at Chapel Hill; and Portola Pharmaceuticals, South San Francisco, CA (P.B.C.).
authors.forename: Yacine
authors.initials: Y
authors.lastname: Boulaftali
authors.affiliation: From the McAllister Heart Institute and Department of Medicine (Y.B., A.P.O., A.B., R.P., C.C., R.H.L., D.S.P., N.M., W.B.), Department of Biochemistry and Biophysics (W.B.), University of North Carolina at Chapel Hill; and Portola Pharmaceuticals, South San Francisco, CA (P.B.C.).
authors.forename: A Phillip
authors.initials: AP
authors.lastname: Owens
authors.affiliation: From the McAllister Heart Institute and Department of Medicine (Y.B., A.P.O., A.B., R.P., C.C., R.H.L., D.S.P., N.M., W.B.), Department of Biochemistry and Biophysics (W.B.), University of North Carolina at Chapel Hill; and Portola Pharmaceuticals, South San Francisco, CA (P.B.C.).
authors.forename: Ashley
authors.initials: A
authors.lastname: Beale
authors.affiliation: From the McAllister Heart Institute and Department of Medicine (Y.B., A.P.O., A.B., R.P., C.C., R.H.L., D.S.P., N.M., W.B.), Department of Biochemistry and Biophysics (W.B.), University of North Carolina at Chapel Hill; and Portola Pharmaceuticals, South San Francisco, CA (P.B.C.).
authors.forename: Raymond
authors.initials: R
authors.lastname: Piatt
authors.affiliation: From the McAllister Heart Institute and Department of Medicine (Y.B., A.P.O., A.B., R.P., C.C., R.H.L., D.S.P., N.M., W.B.), Department of Biochemistry and Biophysics (W.B.), University of North Carolina at Chapel Hill; and Portola Pharmaceuticals, South San Francisco, CA (P.B.C.).
authors.forename: Caterina
authors.initials: C
authors.lastname: Casari
authors.affiliation: From the McAllister Heart Institute and Department of Medicine (Y.B., A.P.O., A.B., R.P., C.C., R.H.L., D.S.P., N.M., W.B.), Department of Biochemistry and Biophysics (W.B.), University of North Carolina at Chapel Hill; and Portola Pharmaceuticals, South San Francisco, CA (P.B.C.).
authors.forename: Robert H
authors.initials: RH
authors.lastname: Lee
authors.affiliation: From the McAllister Heart Institute and Department of Medicine (Y.B., A.P.O., A.B., R.P., C.C., R.H.L., D.S.P., N.M., W.B.), Department of Biochemistry and Biophysics (W.B.), University of North Carolina at Chapel Hill; and Portola Pharmaceuticals, South San Francisco, CA (P.B.C.).
authors.forename: Pamela B
authors.initials: PB
authors.lastname: Conley
authors.affiliation: From the McAllister Heart Institute and Department of Medicine (Y.B., A.P.O., A.B., R.P., C.C., R.H.L., D.S.P., N.M., W.B.), Department of Biochemistry and Biophysics (W.B.), University of North Carolina at Chapel Hill; and Portola Pharmaceuticals, South San Francisco, CA (P.B.C.).
authors.forename: David S
authors.initials: DS
authors.lastname: Paul
authors.affiliation: From the McAllister Heart Institute and Department of Medicine (Y.B., A.P.O., A.B., R.P., C.C., R.H.L., D.S.P., N.M., W.B.), Department of Biochemistry and Biophysics (W.B.), University of North Carolina at Chapel Hill; and Portola Pharmaceuticals, South San Francisco, CA (P.B.C.).
authors.forename: Nigel
authors.initials: N
authors.lastname: Mackman
authors.affiliation: From the McAllister Heart Institute and Department of Medicine (Y.B., A.P.O., A.B., R.P., C.C., R.H.L., D.S.P., N.M., W.B.), Department of Biochemistry and Biophysics (W.B.), University of North Carolina at Chapel Hill; and Portola Pharmaceuticals, South San Francisco, CA (P.B.C.). bergmeie@email.unc.edu.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Bergmeier
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001792:Blood Platelets / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D003094:Collagen / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency* / Q000235:genetics; D006937:Hypercholesterolemia / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D007962:Leukocytes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D010973:Platelet Adhesiveness; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D058925:Receptors, Purinergic P2Y12 / Q000172:deficiency / Q000235:genetics; D013997:Time Factors; D020827:rap1 GTP-Binding Proteins / Q000097:blood
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C548577:P2ry12 protein, mouse; C485927:Rasgrp2 protein, mouse; D011973:Receptors, LDL; D058925:Receptors, Purinergic P2Y12; D003094:Collagen; D020827:rap1 GTP-Binding Proteins
keywords: atherosclerosis; blood platelets; chimera; diet, high-fat; signal transduction