Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E
We studied whether circulating activated platelets and plateletleukocyte aggregates cause the development of atherosclerotic lesions in apolipoprotein-Edeficient (Apoe-/-) mice. Circulating activated platelets bound to leukocytes, preferentially monocytes, to form plateletmonocyte/leukocyte aggregates. Activated platelets and plateletleukocyte 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-selectindeficient, 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 plateletleukocyte/monocyte aggregates promote formation of atherosclerotic lesions. This role of activated platelets in atherosclerosis is attributed to platelet P-selectinmediated delivery of platelet-derived proinflammatory factors to monocytes/leukocytes and the vessel wall.
|Authors:||Huo Y, Schober A, Forlow SB, Smith DF, Hyman MC, Jung S, Littman DR, Weber C, Ley K|
|Journal:||Nat Med 9: 61-67|
|PubMed:||Find in PubMed|