Strain-dependent embryonic lethality and exaggerated vascular remodeling in heparin cofactor II-deficient mice.
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.
Aihara
Ken-ichi
K
Department of Medicine and Bioregulatory Sciences and 21st Century Center of Excellence Program, The University of Tokushima Graduate School of Health Biosciences, Tokushima, Japan.
Azuma
Hiroyuki
H
Akaike
Masashi
M
Ikeda
Yasumasa
Y
Sata
Masataka
M
Takamori
Nobuyuki
N
Yagi
Shusuke
S
Iwase
Takashi
T
Sumitomo
Yuka
Y
Kawano
Hirotaka
H
Yamada
Takashi
T
Fukuda
Toru
T
Matsumoto
Takahiro
T
Sekine
Keisuke
K
Sato
Takashi
T
Nakamichi
Yuko
Y
Yamamoto
Yoko
Y
Yoshimura
Kimihiro
K
Watanabe
Tomoyuki
T
Nakamura
Takashi
T
Oomizu
Akimasa
A
Tsukada
Minoru
M
Hayashi
Hideki
H
Sudo
Toshiki
T
Kato
Shigeaki
S
Matsumoto
Toshio
T
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
D017931:DNA Primers; D015844:Heparin Cofactor II