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.


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.
King
Sarah M
SM
Cardiovascular Biology, Harvard School of Public Health, Boston, Mass, USA.
McNamee
Rachel A
RA
Houng
Aiilyan K
AK
Patel
Rakesh
R
Brands
Michael
M
Reed
Guy L
GL
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001792:Blood Platelets / Q000378:metabolism*; D002340:Carotid Artery Diseases / Q000097:blood* / Q000473:pathology*; D004041:Dietary Fats / Q000494:pharmacology; D004195:Disease Models, Animal; D006965:Hyperplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010974:Platelet Aggregation / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism; D013927:Thrombosis / Q000097:blood*; D017539:Tunica Intima / Q000276:immunology / Q000473:pathology; D014657:Vasculitis / Q000097:blood / Q000473:pathology
D001057:Apolipoproteins E; D004041:Dietary Fats; D012701:Serotonin; D000255:Adenosine Triphosphate
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