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

• Text
• PDF

Abstract

Heparin cofactor II (HCII) specifically inhibits thrombin action at sites of injured arterial wall, and patients with HCII deficiency exhibit advanced 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.

Authors

Ken-ichi Aihara, Hiroyuki Azuma, Masashi Akaike, Yasumasa Ikeda, Masataka Sata, Nobuyuki Takamori, Shusuke Yagi, Takashi Iwase, Yuka Sumitomo, Hirotaka Kawano, Takashi Yamada, Toru Fukuda, Takahiro Matsumoto, Keisuke Sekine, Takashi Sato, Yuko Nakamichi, Yoko Yamamoto, Kimihiro Yoshimura, Tomoyuki Watanabe, Takashi Nakamura, Akimasa Oomizu, Minoru Tsukada, Hideki Hayashi, Toshiki Sudo, Shigeaki Kato, Toshio Matsumoto