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Circulation. 2009 Sep 1;120(9):785-91. doi: 10.1161/CIRCULATIONAHA.108.845461. Epub 2009 Aug 17.

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

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1
Cardiovascular Biology, Harvard School of Public Health, Boston, Mass, USA.

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.

PMID:
19687360
PMCID:
PMC2761818
DOI:
10.1161/CIRCULATIONAHA.108.845461
[Indexed for MEDLINE]
Free PMC Article
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