Heparin cofactor II attenuates vascular remodeling in humans and mice.
Heparin cofactor II (HCII), a serine protease inhibitor (serpin), inactivates thrombin action in the subendothelial layer of the vascular wall. Because a congenitally HCII-deficient patient has been shown to have multiple atherosclerotic lesions, it is hypothesized that HCII plays a pivotal role in the development of vascular remodeling, including atherosclerosis. To clarify this issue, 3 clinical studies concerning plasma HCII activity and atherosclerosis were carried out, and results demonstrated that a higher incidence of in-stent restenosis after percutaneous coronary intervention, maximum carotid arterial plaque thickness, and prevalence of peripheral arterial disease occurred in subjects with low plasma HCII activity. Furthermore, HCII-deficient mice were generated by a gene targeting method to determine the mechanism of the vascular protective action of HCII. Because HCII(-/-) mice were embryonically lethal, we used HCII(+/-) mice and found that they manifested augmentation of intimal hyperplasia and increased thrombosis after cuff or wire injury to the femoral arteries. HCII(+/-) mice with vascular injury showed augmentation of inflammatory cytokines and chemokines and oxidative stress. These abnormal phenotypes of vascular remodeling observed in HCII(+/-) mice were almost restored by human HCII protein supplementation. HCII protects against vascular remodeling, including atherosclerosis, in both humans and mice, and plasma HCII activity might be a predictive biomarker and novel therapeutic target for the prevention of cardiovascular diseases.
Aihara
Ken-ichi
K
Department of Medicine and Bioregulatory Sciences, The University of Tokushima, Graduate School of Health Biosciences, Tokushima, Japan. aihara@clin.med.tokushima-u.ac.jp
D000818:Animals; D050197:Atherosclerosis / Q000209:etiology / Q000473:pathology; D015844:Heparin Cofactor II / Q000502:physiology*; D006801:Humans; D051379:Mice; D044463:Receptor, PAR-1; D013917:Thrombin; D014652:Vascular Diseases / Q000209:etiology / Q000473:pathology
D044463:Receptor, PAR-1; D015844:Heparin Cofactor II; D013917:Thrombin