title: 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.affiliation: Department of Medicine and Bioregulatory Sciences and 21st Century Center of Excellence Program, The University of Tokushima Graduate School of Health Biosciences, Tokushima, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Aihara
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Azuma
authors.forename: Masashi
authors.initials: M
authors.lastname: Akaike
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takamori
authors.forename: Shusuke
authors.initials: S
authors.lastname: Yagi
authors.forename: Takashi
authors.initials: T
authors.lastname: Iwase
authors.forename: Yuka
authors.initials: Y
authors.lastname: Sumitomo
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kawano
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamada
authors.forename: Toru
authors.initials: T
authors.lastname: Fukuda
authors.forename: Takahiro
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Keisuke
authors.initials: K
authors.lastname: Sekine
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nakamichi
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Kimihiro
authors.initials: K
authors.lastname: Yoshimura
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Akimasa
authors.initials: A
authors.lastname: Oomizu
authors.forename: Minoru
authors.initials: M
authors.lastname: Tsukada
authors.forename: Hideki
authors.initials: H
authors.lastname: Hayashi
authors.forename: Toshiki
authors.initials: T
authors.lastname: Sudo
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D001483:Base Sequence; D001808:Blood Vessels / Q000378:metabolism* / Q000473:pathology*; D017931:DNA Primers / Q000235:genetics; D020964:Embryo Loss / Q000235:genetics*; D005260:Female; D018390:Gene Targeting; D005804:Genes, Lethal; D005838:Genotype; D015844:Heparin Cofactor II / Q000172:deficiency* / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011247:Pregnancy
chemical_list: D017931:DNA Primers; D015844:Heparin Cofactor II