Disruption of nuclear vitamin D receptor gene causes enhanced thrombogenicity in mice
Disruption of nuclear vitamin D receptor gene causes enhanced thrombogenicity in mice
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DOI：
10.1074/jbc.m404865200
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发表时间：
2004-08-20
影响因子：
4.8
通讯作者：
Matsumoto, T
中科院分区：
文献类型：
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作者：
Aihara, K;Azuma, H;Matsumoto, T
维生素D代谢物影响与钙稳态、细胞分化和免疫系统调节有关的各种基因的表达。这些基因的表达是由核维生素D受体（VDR）的激活介导的。先前的研究表明，维生素D的激素活性形式，1 α，25-二羟基维生素D3，在培养的单核细胞中发挥抗凝血作用。为了阐明VDR的激活是否在体内发挥任何抗血栓作用，研究人员在高钙饮食的正常血钙水平VDR敲除（KO）小鼠中检测了止血/血栓形成系统，并将其与正常饮食的野生型和低钙VDRKO小鼠进行了比较。与野生型和低钙VDRKO小鼠相比，正常血钙VDRKO小鼠的血小板聚集明显增强。低钙VDRKO小鼠主动脉内皮一氧化氮（NO）合成酶表达和尿NOx排泄减少，而正常血钙VDRKO小鼠无此现象。Northern blot和RT-PCR分析显示，低钙和正钙VDRKO小鼠肝脏抗凝血酶基因表达下调，主动脉、肝脏和肾脏血栓调节蛋白基因表达下调。而与血浆钙水平无关，VDRKO小鼠肝脏和肾脏组织因子mRNA表达上调。此外，无论钙化条件如何，外源性脂多糖注射后，VDRKO小鼠表现出多器官血栓形成加剧。这些结果表明，活化核VDR在体内引起抗血栓作用，并提示VDR系统可能在维持抗血栓稳态中发挥生理作用。
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.