Abstract 1662: Heparin Cofactor II Deficiency Causes Accelerated Thrombosis and Atherosclerosis in Mice
(Background) Enhanced thrombin generation has been recognized as one of major risk factors in the development of thrombosis and atherosclerosis. Heparin cofactor II (HCII) is a serine protease inhibitor that specifically inhibits thrombin action at the site of injured vascular wall. We previously reported that a high level of plasma HCII activity reduces incidences of in-stent restenosis after percutaneous coronary intervention and carotid plaque ( Circulation 2004;109:461–5, 2761–5). However, it is not clear what role HCII plays in the development of thrombosis and atherosclerosis.
(Methods and Results) HCII homozygous mutant mice we generated were embryonic lethal. Therefore, we employed HCII heterozygous mutant (HCII+/−) mice in this study. No structural differences in the femoral artery and aortic root between HCII+/+ mice and HCII+/− mice were observed, whereas prominent neointimal hyperplasia (2.2+/−0.3 mm2 in HCII+/+ mice vs 3.4+/−0.4 mm2 in HCII+/− mice, p<0.05) and higher incidence of arterial occlusion due to thrombosis (20% in HCII+/+ mice vs 40% in HCII+/−mice, p<0.05) were noted in HCII+/− mice after femoral artery wire denudation injury. Whole blood aggregation was enhanced in HCII+/− mice compared to that in HCII+/+ mice. Next, we generated HCII+/− ApoE−/− mice and found that the double-mutant mice manifested lower plasma total cholesterol level than that in HCII+/+ ApoE−/ − mice (298+/−18 mg/dl in HCII+/+ ApoE−/ − mice vs 257+/−18 mg/dl in HCII+/− ApoE−/ − mice, p<0.05). However, atherosclerotic plaque area (1.1+/−0.3 mm2 in HCII+/+ ApoE−/ − mice vs 2.1+/−0.4 mm2 in HCII+/− ApoE−/ −mice, p<0.05), protease activated receptor 1, a major thrombin receptor, and F4/80, a marker of macrophage-positive cells, were significantly increased in the aortic root of HCII+/− ApoE−/ −mice compared to those in HCII+/+ ApoE−/ − mice.
(Conclusions) HCII has protective roles against the formation of thrombosis and atherosclerosis induced by mechanical and metabolic vascular stresses. Therefore, HCII may be a novel therapeutic target for atherothrombosis.