CalDAG-GEFI Deficiency Reduces Atherosclerotic Lesion Development in Mice

Arterioscler Thromb Vasc Biol. 2016 May;36(5):792-9. doi: 10.1161/ATVBAHA.115.306347. Epub 2016 Mar 17.

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.

Keywords: atherosclerosis; blood platelets; chimera; diet, high-fat; signal transduction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / metabolism*
  • Aorta / pathology
  • Aortic Diseases / genetics
  • Aortic Diseases / metabolism
  • Aortic Diseases / pathology
  • Aortic Diseases / prevention & control*
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Atherosclerosis / prevention & control*
  • Blood Platelets / metabolism
  • Chemotaxis, Leukocyte
  • Collagen / metabolism
  • Diet, High-Fat
  • Disease Models, Animal
  • Genetic Predisposition to Disease
  • Guanine Nucleotide Exchange Factors / deficiency*
  • Guanine Nucleotide Exchange Factors / genetics
  • Hypercholesterolemia / genetics
  • Hypercholesterolemia / metabolism
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / pathology
  • Inflammation / prevention & control
  • Leukocytes / metabolism
  • Macrophages / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophil Infiltration
  • Phenotype
  • Plaque, Atherosclerotic*
  • Platelet Adhesiveness
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics
  • Receptors, Purinergic P2Y12 / deficiency
  • Receptors, Purinergic P2Y12 / genetics
  • Time Factors
  • rap1 GTP-Binding Proteins / blood

Substances

  • Guanine Nucleotide Exchange Factors
  • P2ry12 protein, mouse
  • Rasgrp2 protein, mouse
  • Receptors, LDL
  • Receptors, Purinergic P2Y12
  • Collagen
  • rap1 GTP-Binding Proteins