Accelerated atherogenesis and neointima formation in heparin cofactor II–deficient mice

Abstract

Heparin cofactor II (HCII) is a plasma protein that inhibits thrombin when bound to dermatan sulfate or heparin. HCIIdeficient mice are viable and fertile but rapidly develop thrombosis of the carotid artery after endothelial injury. We now report the effects of HCII deficiency on atherogenesis and neointima formation. HCII-null or wild-type mice, both on an apolipoprotein E-null background, were fed an atherogenic diet for 12 weeks. HCII-null mice developed plaque areas in the aortic arch approximately 64% larger than wild-type mice despite having similar plasma lipid and glucose levels. Neointima formation was induced by mechanical dilation of the common carotid artery. Thrombin activity, determined by hirudin binding or chromogenic substrate hydrolysis within 1 hour after injury, was higher in the arterial walls of HCII-null mice than in wild-type mice. After 3 weeks, the median neointimal area was 2-to 3-fold greater in HCII-null than in wild-type mice. Dermatan sulfate administered intravenously within 48 hours after injury inhibited neointima formation in wild-type mice but had no effect in HCII-null mice. Heparin did not inhibit neointima formation. We conclude that HCII deficiency promotes atherogenesis and neointima formation and that treatment with dermatan sulfate reduces neointima formation in an HCII-dependent manner. IntroductionThrombin may participate in formation of atherosclerotic plaques and stimulate proliferation of arterial smooth muscle cells following angioplasty and stent placement. Disruption of the endothelium or the fibrous cap of an atherosclerotic plaque during angioplasty exposes plasma factor VIIa to tissue factor in the arterial wall. 1,2 The factor VIIa/tissue factor complex then converts factor X to factor Xa, which in combination with factor Va converts prothrombin to thrombin. Thrombin converts fibrinogen to fibrin monomers, which polymerize to form a clot, and stimulates platelet aggregation and degranulation by cleaving G-protein-coupled protease activated receptors (specifically, PAR1 and PAR4) on the platelet membrane. 3 The earliest histologic response to stent placement includes local deposition of fibrin and platelets, providing good evidence for thrombin generation in this setting. 4 Thrombin can also activate PAR1 on nearby endothelial cells. 3 In response, the endothelial cells express adhesion molecules and release a variety of mediators that recruit platelets and leukocytes. Therefore, thrombin could play a role in the infiltration of neutrophils, lymphocytes, and macrophages that occurs during the first few days after stent placement. Over the next 2 to 4 weeks, the fibrin and platelets disappear, and restenosis may occur as a result of proliferation of smooth muscle cells and deposition of extracellular matrix in the neointima. 4 Thrombin may induce smooth muscle cell proliferation directly, by activation of PAR1 on these cells, or indirectly, by causing platelets to secrete platelet-derived growth factor.Several of these thrombin-dependent events, including st...

Heparin Cofactor II Attenuates Vascular Remodeling in Humans and Mice

“…All those aberrant phenotype were ameliorated by administration of human purified HCII protein. 48 Vicente et al also reported acceleration of neointimal formation in HCII −/− St Louis mice and HCII +/+ mice 3 weeks after mechanical dilation of the common carotid artery, 49 which is in agreement with our results.…”

“…48 Vicente et al also generated HCII −/− (St Louis) ApoE −/− mice and quantified the observed aortic atherosclerosis. 49 Their double mutant mice manifested greater atherosclerotic plaque areas in the aortic arch compared with that generated by the HCII +/+ ApoE −/− mice. 49 …”

Heparin Cofactor II is an Independent Protective Factor against Peripheral Arterial Disease in Elderly Subjects with Cardiovascular Risk Factors

“…In addition, we and others have recently reported that high plasma HC activity reduced the restenosis of coronary arteries and femoral arteries after stenting 26,45) and attenuated carotid plaque formation 27) in elderly patients. In experimental animal studies using HC -deficient mice, we and Tollefsen's group have shown accelerated vascular remodeling in HC -deficient mice with increased inflammatory cytokines and chemokine gene expression and oxidative stress 29,30) . Taken together, these observations suggest that HC has a pivotal role in protection against "systemic atherosclerosis" in elderly individuals with atherosclerotic risk factors.…”

“…We previously reported an elderly woman with congenital HC deficiency who manifested multiple atherosclerotic disorders 25) , and we have reported the results of clinical studies showing that HC can reduce in-stent restenosis after percutaneous coronary intervention and reduce plaque formation in the carotid artery [26][27][28] . Moreover, we and Tollefsen's group have reported that prominently accelerated vascular remodeling, including atherosclerosis, was observed in HC -deficient mice compared to HC wild-type mice 29,30) . These observations suggested a potential role of HC in counteracting the development of PAD by inhibiting thrombin action in peripheral arteries; however, it is unclear whether HC can contribute to reducing the morbidity of PAD.…”

Plasma heparin cofactor II activity is inversely associated with left atrial volume and diastolic dysfunction in humans with cardiovascular risk factors

“…As HCII can counteract the actions of thrombin at injured vascular walls, we, and others, have investigated and confirmed the protective role of HCII against atherosclerosis in clinical examinations and studies using HCII-deficient mice. [9][10][11][12][13][14][15] As the development of vascular remodeling, including atherosclerosis, has been shown to be closely associated with cardiac remodeling in humans and experimental animal models, we hypothesized that HCII is involved in the process of not only atherosclerosis, but also cardiac remodeling. In order to clarify this issue, we investigated the relationships between plasma HCII activity and surrogate markers with respect to cardiac remodeling in elderly subjects with cardiovascular risk factors.…”