Platelet dense-granule secretion plays a critical role in thrombosis and subsequent vascular remodeling in atherosclerotic mice

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 (HPS 3 ^-/-) markedly reduces platelet dense-granule secretion. HPS3 ^-/- mice have normal platelet counts, platelet morphology, and a-granule number, as well as maximal secretion of the a-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 congenie, 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 FeCl ₃ injury, but ApoE ^-/-, HPS3 ^-/- mice were completely resistant to thrombotic arterial occlusion (P<0.01). Three weeks after injury, neointimal hyperplasia (from a-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,