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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1111.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Thrombocytopenia and Platelet Abnormalities in High-Density Lipoprotein Receptor–Deficient Mice

Vandana S. Dole; Jana Matuskova; Eliza Vasile; Ayce Yesilaltay; Wolfgang Bergmeier; Michael Bernimoulin; Denisa D. Wagner; Monty Krieger

From the Department of Biology (V.S.D., E.V., A.Y., M.K.), Massachusetts Institute of Technology, Cambridge; and Immune Disease Institute and Department of Pathology (J.M., W.B., M.B., D.D.W.), Harvard Medical School, Boston, Mass. Current address for V.S.D.: Charles River Laboratories Inc, Wilmington, Mass. Current address for J.M.: Outcome Sciences, Cambridge, Mass. Current address for W.B.: Department of Medicine and Cardeza Foundation, Thomas Jefferson University, Philadelphia, Pa.

Correspondence to Monty Krieger, Whitehead Professor, Biology Department, Massachusetts Institute of Technology, Room 68-483, 77 Massachusetts Ave, Cambridge, MA 02139. E-mail Krieger{at}MIT.edu

Objective— High-density lipoprotein (HDL) receptor, scavenger receptor class B, type I (SR-BI), mediated cellular uptake of lipoprotein cholesterol controls HDL structure and plasma HDL and biliary cholesterol levels. In SR-BI knockout (KO) mice, an unusually high plasma unesterified-to-total cholesterol ratio (UC:TC) and abnormally large HDL particles apparently contribute to pathology, including female infertility, susceptibility to atherosclerosis and coronary heart disease, and anemia. Here we examined the influence of SR-BI deficiency on platelets.

Methods and Results— The high plasma UC:TC ratio in SR-BI KO mice was correlated with platelet abnormalities, including high cholesterol content, abnormal morphologies, high clearance rates, and thrombocytopenia. One day after platelets from wild-type mice were infused into SR-BI KO mice, they exhibited abnormally high cholesterol content and clearance rates similar to those of endogenous platelets. Platelets from SR-BI KO mice exhibited in vitro a blunted aggregation response to the agonist ADP but a normal response to PAR4.

Conclusions— In SR-BI KO mice abnormal circulating lipoproteins, particularly their high UC:TC ratio—rather than the absence of SR-BI in platelets themselves—induce defects in platelet structure and clearance, together with a mild defect in function.

The high UC:TC ratio associated with SR-BI deficiency in mice is correlated with platelet abnormalities, including high cholesterol content, abnormal morphologies, high clearance rates, thrombocytopenia, and a minor defect in in vitro aggregation (blunted response to ADP).

Key Words: HDL receptor • SR-BI • platelet • thrombocytopenia • clearance