Strain-dependent embryonic lethality and exaggerated vascular remodeling in heparin cofactor II-deficient mice
Strain-dependent embryonic lethality and exaggerated vascular remodeling in heparin cofactor II-deficient mice
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DOI：
10.1172/jci27095
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发表时间：
2007-06-01
影响因子：
15.9
通讯作者：
Matsumoto, Toshio
中科院分区：
文献类型：
--
作者：
Aihara, Ken-ichi;Azuma, Hiroyuki;Matsumoto, Toshio
肝素辅因子II（HCII）特异性抑制凝血酶在受损动脉壁部位的作用，HCH缺乏的患者表现出晚期动脉粥样硬化。然而，在体内的影响和HCH在血管重塑过程中的作用的分子机制仍然难以捉摸。为了阐明六氯环己烷在血管重塑中的作用，我们通过基因打靶产生了HCII缺陷小鼠。与以前的报告相反，HCII-/-小鼠是胚胎致死的。在HCII+/-小鼠中，在管套囊和导丝血管损伤后观察到显著的内膜增生伴细胞增殖增加。HCII+/-小鼠增厚的血管壁中蛋白酶激活受体1阳性（PAR-1阳性）细胞的数量增加，表明该区域的凝血酶作用增强。袖带损伤还增加了HCII+/-小鼠血管壁中炎性细胞因子和趋化因子的表达水平。通过补充人类六氯环己烷，HCII+/-小鼠血管损伤的内膜增生消失。此外，HCH缺乏导致apoE-KO小鼠主动脉斑块形成加速，PAR-1表达增加，氧化应激增加。这些结果表明，六氯环己烷通过抑制凝血酶的作用，防止凝血酶诱导的受损血管壁的重塑，并表明六氯环己烷对动脉粥样硬化有潜在的治疗作用，而不会引起凝血障碍。
Heparin cofactor II (HCII) specifically inhibits thrombin action at sites of injured arterial wall, and patients with HCH deficiency exhibit advanced atherosclerosis. However, the in vivo effects and the molecular mechanism underlying the action of HCH during vascular remodeling remain elusive. To clarify the role of HCH 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 HCH supplementation. Furthermore, HCH deficiency caused acceleration of aortic plaque formation with increased PAR-1 expression and oxidative stress in apoE-KO mice. These results demonstrate that HCH protects against thrombin-induced remodeling of an injured vascular wall by inhibiting thrombin action and suggest that HCH is potentially therapeutic against atherosclerosis without causing coagulatory disturbance.