Impact of antithrombin deficiency in thrombogenesis: lipopolysaccharide and stress-induced thrombus formation in heterozygous antithrombin-deficient mice

Yanada, Masamitsu; Kojima, Tetsuhito; Ishiguro, Kazuhiro; Nakayama, Yasuichi; Yamamoto, Kōji; Matsushita, Tadashi; Kadomatsu, Kenji; Nishimura, Masahiko; Muramatsu, Takashi; Saito, Hidehiko

doi:10.1182/blood.v99.7.2455

Cited by 57 publications

(32 citation statements)

References 19 publications

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“…Recently, AT-deficient mice were generated by gene targeting, and homozygous AT-null mice were shown to be prenatally lethal because of extensive thrombosis in the myocardium and liver sinusoids along with generally massive bleeding (20). In addition, heterozygous AT-deficient mice showed a tendency toward thrombus formation in the kidney after LPS injection (21). The present observations suggest that the vitamin D/VDR system may affect AT activity through transcriptional control of AT gene expression.…”

Section: Figmentioning

confidence: 79%

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

Aihara¹,

Azuma²,

Akiyama³

et al. 2004

Journal of Biological Chemistry

236

161

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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.

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Section: Figmentioning

confidence: 79%

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

Aihara¹,

Azuma²,

Akiyama³

et al. 2004

Journal of Biological Chemistry

236

161

View full text Add to dashboard Cite

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“…LPS-induced fibrin deposition has been consistently reported in the kidney where it is confined to glomerular and peritubular capillaries in different species (10,41,42). Apoptotic cell death has been demonstrated in bovine glomerular endothelial cells subjected to LPS (22).…”

mentioning

confidence: 90%

Hydrogel-embedded endothelial progenitor cells evade LPS and mitigate endotoxemia

Ghaly

Rabadi

Weber

et al. 2011

American Journal of Physiology-Renal Physiology

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“…14 Moreover, endotoxemicAT-III + / − and PC + / − heterozygous mice exhibited increased fibrin deposition and mortality compared with wild-type (WT) controls, presumably due to reduced levels of the anticoagulants. 15,16 In a lethal baboon model of Escherichia coli-induced sepsis, inhibition of the TF-factor VIIa (FVIIa) complex with either an inhibitory anti-TF monoclonal antibody, active siteinhibited FVIIa (FVIIai), or TFPI-1 decreased coagulation and prevented death. 3,17,18 Importantly, FVIIai and TFPI-1 reduced the expression of the inflammatory mediators interleukin-6 (IL-6) and IL-8 at later times (more than 4 hours after administration of E coli) but did not affect tumor necrosis factor-α (TNF-α) expression, 3,18 indicating that IL-6 expression can be used to monitor crosstalk between coagulation and inflammation.…”

Section: Introductionmentioning

confidence: 99%

Role of tissue factor and protease-activated receptors in a mouse model of endotoxemia

Pawliński

Pedersen

Schabbauer

et al. 2004

Blood

282

279

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Sepsis is associated with a systemic activation of coagulation and an excessive inflammatory response. Anticoagulants have been shown to inhibit both coagulation and inflammation in sepsis. In this study, we used both genetic and pharmacologic approaches to analyze the role of tissue factor and protease-activated receptors in coagulation and inflammation in a mouse endotoxemia model. We used mice expressing low levels of the procoagulant molecule, tissue factor (TF), to analyze the effects of TF deficiency either in all tissues or selectively in hematopoietic cells. Low TF mice had reduced coagulation, inflammation, and mortality compared with control mice. Similarly, a deficiency of TF expression by hematopoietic cells reduced lipopolysaccharide (LPS)-induced coagulation, inflammation, and mortality. Inhibition of the downstream coagulation protease, thrombin, reduced fibrin deposition and prolonged survival without affecting inflammation. Deficiency of either protease activated receptor-1 (PAR-1) or protease activated receptor-2 (PAR-2) alone did not affect inflammation or survival. However, a combination of thrombin inhibition and PAR-2 deficiency reduced inflammation and mortality. These data demonstrate that hematopoietic cells are the major pathologic site of TF expression during endotoxemia and suggest that multiple protease-activated receptors mediate crosstalk between coagulation and inflammation.

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Impact of antithrombin deficiency in thrombogenesis: lipopolysaccharide and stress-induced thrombus formation in heterozygous antithrombin-deficient mice

Cited by 57 publications

References 19 publications

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

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

Hydrogel-embedded endothelial progenitor cells evade LPS and mitigate endotoxemia

Role of tissue factor and protease-activated receptors in a mouse model of endotoxemia

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