Strain-dependent embryonic lethality and exaggerated vascular remodeling in heparin cofactor II–deficient mice

Abstract

atherosclerosis. However, the in vivo effects and the molecular mechanism underlying the action of HCII during vascular remodeling remain elusive. To clarify the role of HCII in vascular remodeling, we generated HCII-deficient mice by gene targeting. In contrast to a previous report, HCII -/-mice were embryonically lethal. In HCII +/-mice, prominent intimal hyperplasia with increased cellular proliferation was observed after tube cuff and wire vascular injury. The number of protease-activated receptor-1-positive (PAR-1-positive) cells was increased in the thickened vascular wall of HCII +/-mice, suggesting enhanced thrombin action in this region. Cuff injury also increased the expression levels of inflammatory cytokines and chemokines in the vascular wall of HCII +/-mice. The intimal hyperplasia in HCII +/-mice with vascular injury was abrogated by human HCII supplementation. Furthermore, HCII deficiency caused acceleration of aortic plaque formation with increased PAR-1 expression and oxidative stress in apoE-KO mice. These results demonstrate that HCII protects against thrombin-induced remodeling of an injured vascular wall by inhibiting thrombin action and suggest that HCII is potentially therapeutic against atherosclerosis without causing coagulatory disturbance.

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 was stored at 80 until use. Plasma HC and AT activities were measured as previously described 28,29) .…”

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

“…Enlarged LAV has been shown to be associated with inflammation and atherosclerosis. 26,27 As cuff-tube placement around the femoral artery caused increases in the gene expression levels of inflammatory cytokines and chemokines, such as interleukin-1b and -6 and monocyte chemoattractant protein-1 in HCII-deficient mice compared with the levels in wild-type mice, 14 there is a possibility that HCII prevents LA enlargement partly through its anti-inflammatory potency leading to attenuation of left atrial remodeling. As LAV is an indicator of the burden of diastolic dysfunction, even in patients without atrial fibrillation or significant valvular heart disease, 28 our results indicated that plasma HCII activity could be involved in the pathogenesis of left ventricular diastolic dysfunction.…”

“…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.…”