Disruption of Nuclear Vitamin D Receptor Gene Causes Enhanced Thrombogenicity in Mice

Abstract

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, 1␣,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.

Vitamin D level and extent of coronary stenotic lesions in patients with first acute myocardial infarction

“…It directly or indirectly regulates the expression of a number of proteins relevant to the arterial wall, such as vascular endothelial growth factor, matrix metalloproteinase type 9, elastin, and type I collagen. Probably, vitamin D has also an impact on the cardiovascular system by exerting anticoagulant and antifibrotic activity [12], thereby preventing thrombosis.…”

1,25(OH)2D3 blocks TNF-induced monocytic tissue factor expression by inhibition of transcription factors AP-1 and NF-κB

“…Several subsequent studies have reported that the vitamin D/VDR system plays a physiological role in vivo in the maintenance of antithrombotic homeostasis. Aihara et al 15 demonstrated that upregulation of TF and downregulation of TM in the aorta, liver, and kidney were related to enhanced thrombogenicity in VDR knockout mice. 1,25(OH) 2 D 3 was effective against DIC in a rat model induced by LPS.…”

Vitamin D intake and risk of CVD and all-cause mortality: evidence from the Caerphilly Prospective Cohort Study

“…Several potential mechanisms for the observed inverse association of vitamin D intake with serum TAG have been proposed, namely the ability of vitamin D to modulate the growth of vascular smooth muscle cells (25) , antithrombotic homeostasis (26) and inflammation markers of CVD (27) . Furthermore, previous studies (28,29) have reported that vitamin D status (plasma 25-hydroxyvitamin D) is inversely associated with TAG concentration; thus, to better clarify how vitamin D status is related to CVD risk, future biomarker studies of CVD and plasma 25-hydroxyvitamin D are warranted.…”