Strain-dependent embryonic lethality and exaggerated vascular remodeling in heparin cofactor II–deficient mice
Ken-ichi Aihara, … , Shigeaki Kato, Toshio Matsumoto
Ken-ichi Aihara, … , Shigeaki Kato, Toshio Matsumoto
Published June 1, 2007
Citation Information: J Clin Invest. 2007;117(6):1514-1526. https://doi.org/10.1172/JCI27095.
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Strain-dependent embryonic lethality and exaggerated vascular remodeling in heparin cofactor II–deficient mice

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

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Figure 1

Targeted disruption of murine HCII gene, genotyping, and karyotypes of HCII-mutant mice.

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Targeted disruption of murine HCII gene, genotyping, and karyotypes of H...
(A) Genomic locus, targeting vector, and predicted targeting locus are illustrated. External (probe A) and internal (probe B) probes were used for Southern blot analysis. Two sets of PCR primers for detecting the 480-bp WT allele and 740-bp mutant allele were employed for genotyping. (B) Southern blot analysis of murine genomic DNA. A 5-kbp HindIII fragment denotes the homologous recombinant allele in probe A as an external probe, and a single 7-kbp HindIII fragment denotes the homologous recombinant allele without random integration in probe B as an internal probe. (C) Genotyping PCR. The mutant allele yielded a 740-bp band, and the WT allele yielded a 480-bp band. (D) Karyotype analysis of HCII+/– male and female mice. Chromosomes of splenic lymphocytes in both male and female HCII mutant mice showed normal karyotypes.