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(Circulation. 2009;120:785-791.)
© 2009 American Heart Association, Inc.

Vascular Medicine

Platelet Dense-Granule Secretion Plays a Critical Role in Thrombosis and Subsequent Vascular Remodeling in Atherosclerotic Mice

Sarah M. King, PhD; Rachel A. McNamee, BS; Aiilyan K. Houng, BS; Rakesh Patel, MD; Michael Brands, PhD; Guy L. Reed, MS, MD

From Cardiovascular Biology (S.M.K., G.L.R.), Harvard School of Public Health, Boston, Mass; Department of Physiology (M.B.) and Cardiovascular Center (R.A.M., R.P., G.L.R.), Medical College of Georgia, Augusta; and University of Tennessee Health Science Center (A.K.H., G.L.R.), Memphis.

Correspondence to Guy L. Reed, University of Tennessee Health Sciences Center, Coleman D334, 956 Court Ave, Memphis, TN 38163.

Received December 22, 2008; accepted June 15, 2009.

Background— Platelet aggregation plays a critical role in myocardial infarction and stroke; however, the role of platelet secretion in atherosclerotic vascular disease is poorly understood. Therefore, we examined the hypothesis that platelet dense-granule secretion modulates thrombosis, inflammation, and atherosclerotic vascular remodeling after injury.

Methods and Results— Functional deletion of the Hermansky-Pudlak syndrome 3 gene (HPS3^–/–) markedly reduces platelet dense-granule secretion. HPS3^–/– mice have normal platelet counts, platelet morphology, and -granule number, as well as maximal secretion of the -granule marker P-selectin; however, their capacity to form platelet-leukocyte aggregates is significantly reduced (P<0.05). To examine the role of platelet dense-granule secretion in these processes, atherosclerosis-prone mice with combined genetic deficiency of apolipoprotein E and HPS3 (ApoE^–/–, HPS3^–/–) were compared with congenic, atherosclerosis-prone mice with normal platelet secretion (ApoE^–/–, HPS3^+/+). After 16 to 18 weeks on a high-fat diet, both groups of mice had similar fasting cholesterol levels and body weight. Carotid arteries of ApoE^–/–, HPS3^+/+ mice thrombosed rapidly after FeCl₃ injury, but ApoE^–/–, HPS3^–/– mice were completely resistant to thrombotic arterial occlusion (P<0.01). Three weeks after injury, neointimal hyperplasia (from -smooth muscle actin–positive cells) was significantly less (P<0.001) in arteries from ApoE^–/–, HPS3^–/– mice. In ApoE^–/–, HPS3^–/– mice, there were also pronounced reductions in arterial inflammation, as indicated by a 74% decrease in CD45-positive leukocytes (P<0.01) and a 73% decrease in Mac-3–positive macrophages (P<0.05).

Conclusions— In atherosclerotic mice, reduced platelet dense-granule secretion is associated with marked protection against the development of arterial thrombosis, inflammation, and neointimal hyperplasia after vascular injury.

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Circulation 2009 120: 717. [Extract] [Full Text]