Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E.
We studied whether circulating activated platelets and platelet-leukocyte aggregates cause the development of atherosclerotic lesions in apolipoprotein-E-deficient (Apoe(-/-)) mice. Circulating activated platelets bound to leukocytes, preferentially monocytes, to form platelet-monocyte/leukocyte aggregates. Activated platelets and platelet-leukocyte aggregates interacted with atherosclerotic lesions. The interactions of activated platelets with monocytes and atherosclerotic arteries led to delivery of the platelet-derived chemokines CCL5 (regulated on activation, normal T cell expressed and secreted, RANTES) and CXCL4 (platelet factor 4) to the monocyte surface and endothelium of atherosclerotic arteries. The presence of activated platelets promoted leukocyte binding of vascular cell adhesion molecule-1 (VCAM-1) and increased their adhesiveness to inflamed or atherosclerotic endothelium. Injection of activated wild-type, but not P-selectin-deficient, platelets increased monocyte arrest on the surface of atherosclerotic lesions and the size of atherosclerotic lesions in Apoe(-/-) mice. Our results indicate that circulating activated platelets and platelet-leukocyte/monocyte aggregates promote formation of atherosclerotic lesions. This role of activated platelets in atherosclerosis is attributed to platelet P-selectin-mediated delivery of platelet-derived proinflammatory factors to monocytes/leukocytes and the vessel wall.
Huo
Yuqing
Y
Department of Biomedical Engineering and Cardiovascular Research Center, University of Virginia, Health Science Center, Charlottesville, Virginia, USA.
Schober
Andreas
A
Forlow
S Bradley
SB
Smith
David F
DF
Hyman
Matthew Craig
MC
Jung
Steffen
S
Littman
Dan R
DR
Weber
Christian
C
Ley
Klaus
K
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology; D001792:Blood Platelets / Q000378:metabolism*; D016893:Carotid Stenosis / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism; D015539:Platelet Activation; D010978:Platelet Factor 4 / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D001057:Apolipoproteins E; D018946:Chemokine CCL5; D019007:P-Selectin; D019010:Vascular Cell Adhesion Molecule-1; D010978:Platelet Factor 4