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

Abstract:

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 alpha-granule number, as well as maximal secretion of the alpha-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 FeCl(3) injury, but ApoE(-/-), HPS3(-/-) mice were completely resistant to thrombotic arterial occlusion (P<0.01). Three weeks after injury, neointimal hyperplasia (from alpha-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.

journal_name

Circulation

journal_title

Circulation

authors

King SM,McNamee RA,Houng AK,Patel R,Brands M,Reed GL

doi

10.1161/CIRCULATIONAHA.108.845461

subject

Has Abstract

pub_date

2009-09-01 00:00:00

pages

785-91

issue

9

eissn

0009-7322

issn

1524-4539

pii

CIRCULATIONAHA.108.845461

journal_volume

120

pub_type

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