Disruption of nuclear vitamin D receptor gene causes enhanced thrombogenicity in mice.
Vitamin D metabolites influence the expression of various genes involved in calcium homeostasis, cell differentiation, and regulation of the immune system. Expression of these genes is mediated by the activation of the nuclear vitamin D receptor (VDR). Previous studies have shown that a hormonally active form of vitamin D, 1alpha,25-dihydroxyvitamin D3, exerts anticoagulant effects in cultured monocytic cells. To clarify whether activation of VDR plays any antithrombotic actions in vivo, hemostatic/thrombogenic systems were examined in normocalcemic VDR knock-out (KO) mice on a high calcium diet and compared with wild type and hypocalcemic VDRKO mice that were fed a regular diet. Platelet aggregation was enhanced significantly in normocalcemic VDRKO mice compared with wild type and hypocalcemic VDRKO mice. Aortic endothelial nitric-oxide (NO) synthase expression and urinary NOx excretions were reduced in hypocalcemic VDRKO mice, but not in normocalcemic VDRKO mice. Northern blot and RT-PCR analyses revealed that the gene expression of antithrombin in the liver as well as that of thrombomodulin in the aorta, liver and kidney was down-regulated in hypo- and normocalcemic VDRKO mice. Whereas tissue factor mRNA expression in the liver and kidney was up-regulated in VDRKO mice regardless of plasma calcium level. Furthermore, VDRKO mice manifested an exacerbated multi-organ thrombus formation after exogenous lipopolysaccharide injection regardless of the calcemic conditions. These results demonstrate that activation of nuclear VDR elicits antithrombotic effects in vivo, and suggest that the VDR system may play a physiological role in the maintenance of antithrombotic homeostasis.
Aihara
Ken-ichi
K
Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, Japan. aihara@clin.med.tokushima-u.ac.jp
Azuma
Hiroyuki
H
Akaike
Masashi
M
Ikeda
Yasumasa
Y
Yamashita
Michiko
M
Sudo
Toshiki
T
Hayashi
Hideki
H
Yamada
Yoshihisa
Y
Endoh
Fuminari
F
Fujimura
Mitsunori
M
Yoshida
Tomonori
T
Yamaguchi
Hiroshi
H
Hashizume
Shunji
S
Kato
Midori
M
Yoshimura
Kimihiro
K
Yamamoto
Yoko
Y
Kato
Shigeaki
S
Matsumoto
Toshio
T
D000818:Animals; D001777:Blood Coagulation / Q000235:genetics* / Q000502:physiology; D002118:Calcium / Q000008:administration & dosage / Q000378:metabolism; D004032:Diet; D015536:Down-Regulation; D017353:Gene Deletion; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009928:Organ Specificity; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism; D013917:Thrombin / Q000096:biosynthesis; D018180:Thrombomodulin / Q000096:biosynthesis
D018167:Receptors, Calcitriol; D018180:Thrombomodulin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D013917:Thrombin; D002118:Calcium