King Sarah M, McNamee Rachel A, Houng Aiilyan K, Patel Rakesh, Brands Michael, Reed Guy L
Cardiovascular Biology, Harvard School of Public Health, Boston, Mass, USA.
Circulation. 2009 Sep 1;120(9):785-91. doi: 10.1161/CIRCULATIONAHA.108.845461. Epub 2009 Aug 17.
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.
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).
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.
血小板聚集在心肌梗死和中风中起关键作用；然而，血小板分泌在动脉粥样硬化性血管疾病中的作用却鲜为人知。因此，我们检验了以下假设：血小板致密颗粒分泌可调节损伤后血栓形成、炎症及动脉粥样硬化性血管重塑。
赫尔曼斯基-普德拉克综合征3基因（HPS3）功能缺失（HPS3-/-）显著减少血小板致密颗粒分泌。HPS3-/-小鼠血小板计数、血小板形态及α颗粒数量正常，α颗粒标志物P-选择素的最大分泌量也正常；然而，它们形成血小板-白细胞聚集体的能力显著降低（P<0.05）。为研究血小板致密颗粒分泌在这些过程中的作用，将载脂蛋白E和HPS3基因联合缺陷的动脉粥样硬化易感小鼠（ApoE-/-，HPS3-/-）与血小板分泌正常的同基因动脉粥样硬化易感小鼠（ApoE-/-，HPS3+/+）进行比较。高脂饮食16至18周后，两组小鼠的空腹胆固醇水平和体重相似。ApoE-/-，HPS3+/+小鼠的颈动脉在FeCl3损伤后迅速形成血栓，但ApoE-/-，HPS3-/-小鼠对血栓性动脉闭塞完全具有抵抗力（P<0.01）。损伤3周后，ApoE-/-，HPS3-/-小鼠动脉中的新生内膜增生（来自α平滑肌肌动蛋白阳性细胞）显著减少（P<0.001）。在ApoE-/-，HPS3-/-小鼠中，动脉炎症也明显减轻，表现为CD45阳性白细胞减少74%（P<0.01），Mac-3阳性巨噬细胞减少73%（P<0.05）。
在动脉粥样硬化小鼠中，血小板致密颗粒分泌减少与显著预防血管损伤后动脉血栓形成、炎症及新生内膜增生有关。
