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 (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,
| Original language | English (US) |
|---|---|
| Pages (from-to) | 785-791 |
| Number of pages | 7 |
| Journal | Circulation |
| Volume | 120 |
| Issue number | 9 |
| DOIs | |
| State | Published - Nov 12 2009 |
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Keywords
- Arteriosclerosis
- Atherosclerosis
- Carotid arteries
- Platelet-derived factors
- Platelets
- Thrombosis
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)
Cite this
Platelet dense-granule secretion plays a critical role in thrombosis and subsequent vascular remodeling in atherosclerotic mice. / King, Sarah M.; McNamee, Rachel A.; Houng, Aiilyan K.; Patel, Rakesh; Brands, Michael; Reed, Guy L.
In: Circulation, Vol. 120, No. 9, 12.11.2009, p. 785-791.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Platelet dense-granule secretion plays a critical role in thrombosis and subsequent vascular remodeling in atherosclerotic mice
AU - King, Sarah M.
AU - McNamee, Rachel A.
AU - Houng, Aiilyan K.
AU - Patel, Rakesh
AU - Brands, Michael
AU - Reed, Guy L.
PY - 2009/11/12
Y1 - 2009/11/12
N2 - 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,
AB - 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,
KW - Arteriosclerosis
KW - Atherosclerosis
KW - Carotid arteries
KW - Platelet-derived factors
KW - Platelets
KW - Thrombosis
UR - http://www.scopus.com/inward/record.url?scp=70349304085&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70349304085&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.108.845461
DO - 10.1161/CIRCULATIONAHA.108.845461
M3 - Article
C2 - 19687360
AN - SCOPUS:70349304085
VL - 120
SP - 785
EP - 791
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 9
ER -