Heparin-like glycosaminoglycan is a receptor for Antithrombin III-dependent but not for thrombin-dependent prostacyclin production in human endothelial cells

Horie, Shuichi; Ishii, Hidemi; Kazama, Mutsuyoshi

doi:10.1016/0049-3848(90)90113-q

Cited by 124 publications

(84 citation statements)

References 24 publications

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“…AT has been shown to promote the endothelial release of PGI 2 by interacting with heparinlike GAGs on the endothelial cell surface in vitro 4,5 and in vivo. 6 The effects induced by AT in this rat model of septic shock appeared to be mediated by PGI 2 , which may have been released from the endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…In this process, interaction of AT with the endothelial heparinlike GAGs is critical for the promotion of the endothelial release of PGI 2 . 5,6 Further studies are necessary to clarify the mechanism(s)…”

Section: Discussionmentioning

confidence: 99%

“…1 Patients with congenital AT deficiency and those with the variant AT that lacks affinity for GAGs develop thrombosis, showing the importance of the interaction of AT with the endothelial cell surface GAGs for regulation of the coagulation cascade. 2,3 AT has been shown to promote endothelial release of prostacyclin (PGI 2 ) by interacting with the endothelial surface GAGs in vitro 4,5 and in vivo. 6 PGI 2 potently inhibits platelet aggregation 7 and induces vasodilation, 8 thereby maintaining proper organ microcirculation.…”

Section: Introductionmentioning

confidence: 99%

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Antithrombin prevents endotoxin-induced hypotension by inhibiting the induction of nitric oxide synthase in rats

Okajima

Uchiba

Harada

et al. 2002

Blood

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Antithrombin (AT) prevents Escherichia coli-induced hypotension in animal models of sepsis, and it further reduces the mortality of patients with septic shock. In the present study, we examined whether AT may prevent the endotoxin (ET)-induced hypotension by promoting the endothelial release of prostacyclin (PGI 2 ) in rats. Intravenous administration of AT (250 U/kg) prevented both hypotension and the increases in plasma levels of NO 2 ؊ / NO 3 ؊ in rats given ET. Lung expression of messenger RNA (mRNA) for tumor necrosis factor-␣ (TNF-␣) was transiently increased after ET administration, followed by the increases in lung tissue levels of TNF-␣. Both the lung activity of the inducible form of nitric oxide synthase (iNOS) and the lung expression of iNOS mRNA in animals administered ET were gradually increased after the TNF-␣ mRNA expression had peaked. Administration of AT significantly inhibited these increases. Neither DEGR-F.Xa, a selective inhibitor of thrombin generation, nor Trp 49 -modified AT, which is not capable of promoting the endothelial release of PGI 2 , showed any effects on these changes induced by ET. Administration of antirat TNF-␣ antibody produced effects similar to those induced by AT. Indomethacin pretreatment abrogated the effects induced by AT. Iloprost, a stable derivative of PGI 2 , produced effects similar to those of AT. These findings suggested that AT prevents the ET-induced hypotension by inhibiting the induction of iNOS through inhibiting TNF-␣ production. These effects of AT could be mediated by the promotion of endothelial release of PGI 2 and might at least partly explain the therapeutic effects for septic shock. IntroductionAntithrombin (AT) is an important serine protease inhibitor of the coagulation system. 1 Inhibition by AT of thrombin and the other serine proteases generated from the coagulation cascade is markedly accelerated by its interaction with the endothelial surface glycosaminoglycans (GAGs). 1 Patients with congenital AT deficiency and those with the variant AT that lacks affinity for GAGs develop thrombosis, showing the importance of the interaction of AT with the endothelial cell surface GAGs for regulation of the coagulation cascade. 2,3 AT has been shown to promote endothelial release of prostacyclin (PGI 2 ) by interacting with the endothelial surface GAGs in vitro 4,5 and in vivo. 6 PGI 2 potently inhibits platelet aggregation 7 and induces vasodilation, 8 thereby maintaining proper organ microcirculation. In addition, PGI 2 inhibits the endotoxin (ET)-induced monocytic production of tumor necrosis factor-␣ (TNF-␣). 9 TNF-␣ plays a role in the propagation of inflammation by activating neutrophils 10 and by inducing nitric oxide synthase (NOS). 11 Excessive production of NO by the inducible form of NOS (iNOS) plays critical roles in the pathophysiology of septic shock. 12 Septic shock, associated with infection with Gram-negative and Gram-positive bacteria and with fungus, is characterized by hypotension, organ dysfunction, and disseminated intravascular c...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Antithrombin prevents endotoxin-induced hypotension by inhibiting the induction of nitric oxide synthase in rats

Okajima

Uchiba

Harada

et al. 2002

Blood

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“…Direct binding of ATIII to endothelial cells has been demonstrated by Stern et al 34 in bovine aortic segments. It has been shown by other authors that ATIII, in vitro 35,36 or in vivo, 37 stimulates the production of PGI 2 from endothelial cells, which might be explained by its binding to the glycosaminoglycan structure. As PGI 2 inhibits platelet aggregation and promotes vasodilation in lung arteries, this might explain ATIII's beneficial effects on sepsis.…”

Section: Discussionmentioning

confidence: 99%

Influence of Antithrombin III on Coagulation and Inflammation in Porcine Septic Shock

Dickneite¹,

Leithäuser²

1999

ATVB

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Abstract-The physiological inhibitor of thrombin, antithrombin III (ATIII, Kybernin P) was investigated for its antiinflammatory and anticoagulant effects in a pig model of septic shock. Pigs were infused with a dose of 0.25 g ⅐ kg Ϫ1 ⅐ h Ϫ1 of lipopolysaccharide (LPS) over a period of 3 hours. Animals developed systemic inflammation, disseminated intravascular coagulation (DIC), organ failure and cardiovascular abnormalities, namely pulmonary hypertension and systemic hypotension. Twenty septic pigs were allocated to 2 study groups, treated either with ATIII (nϭ10) or placebo (nϭ10). ATIII was administered as a 250-U/kg IV bolus infusion for 30 minutes (Ϫ60 to Ϫ30 minutes) followed by a single IV bolus of 125 U/kg (tϭ0) and a second 30-minute infusion of 250 U/kg (120 to 150 minutes). ATIII significantly prevented the development of a DIC; the increase in fibrin monomers (placebo, 11.4Ϯ9.1 reciprocal titers, at 6 hours) was completely overcome by ATIII (PϽ0.05). ATIII significantly prevented the increase in thromboxane (TXB 2 ) levels, which were 809Ϯ287 pg/mL in the placebo and 420Ϯ174 pg/mL in the verum group after 6 hours (PϽ0.02). On the other hand, ATIII had no influence on TNF levels. In a lethal study with an increased dose of LPS (0.5 g ⅐ kg Ϫ1 ⅐ h Ϫ1 ). A significant reduction in mortality was observed in the ATIII group (0 of 7) compared with the placebo group (4 of 6) (PϽ0.05, 2 test) a significant reduction of pulmonary hypertension (placebo, 42.0Ϯ11.1 mm Hg; ATIII, 23.6Ϯ7.5 mm Hg, PϽ0.05), but no effect on systemic hypotension, was noted in the ATIII group. It was thus concluded that modulation of the procoagulatory state by substitution of ATIII results in a late beneficial antiinflammatory effect in this model of septic shock. Key Words: lipopolysaccharide Ⅲ disseminated intravascular coagulation Ⅲ pulmonary hypertension Ⅲ soluble fibrin monomers Ⅲ thromboxane S epsis as a severe complication of infection is characterized by systemic inflammation, activation of proteolytic cascades, coagulation abnormalities (DIC) and a gradually developing hypodynamic status with impaired organ perfusion, and finally death in a septic shock. Lung circulation in septic shock is characterized by hypertension and increased pulmonary resistance, resulting in low cardiac output, and, frequently, in lung failure. Mortality in septic shock is usually high, ie, in the range of 40% to 50%. 1 If associated with multi-organ dysfunction such as respiratory or renal failure, mortality might exceed 90%. 2 The initiating event for the development of sepsis is the activation of macrophages by lipopolysaccharide (LPS) liberated from Gram-negative bacteria via binding to its surface receptor CD14. 3 However, sepsis might be induced by other agents, such as Grampositive bacteria, fungi or viruses. The initial excessive secretion of cytokine mediators such as interleukin 1 (IL-1) and tumor necrosis factor (TNF-␣) is followed by the activation of biological cascades including the coagulation, the complement, the fibrinolytic and the...

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“…Average AT activity on both days was still within the range of reference values. AT is a strong serine protease inhibitor that inactivates thrombin and the clotting factors XII, IX and X and also has anti-inflammatory properties resulting from its stimulation of prostacyclin synthesis (31,32).…”

Section: Discussionmentioning

confidence: 99%

L-carnitine and cancer cachexia. II. Effects of lipid emulsion used in total parenteral nutrition on parameters of hemostasis and inflammatory state in L-carnitine deficiency in myocytes

et al. 2012

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Abstract. Cancer cachexia (CC), a progressive loss of body mass, leads to malnutrition and deficiencies of essential substances including polyunsaturated fatty acids (PUFAs) and L-carnitine (LC). The availability of these 2 compounds determines the rate of eicosanoid synthesis, which modulates inflammatory processes and hemostasis. We compared the effects of administration of emulsions containing long chain triglycerides (LCTs) relative to a 50:50 mix of medium chain triglycerides (MCTs) with LCTs on hemostasis and inflammatory reactions in patients with CC. The study was conducted on 50 patients with CC (23 women, 27 men) aged 66±11 years with a mean loss in body weight of 21±9% in the previous 6 months. Twenty patients received MCTs/LCTs while 30 received LCTs. Total parenteral nutrition (TPN) was administered using the 'all in one' method (25 kcal/kg/day, protein 1.2 g/kg/day). Selected parameters of coagulation and inflammatory state were evaluated on Days 1, 5, 7 and 11 of TPN. Initial concentrations of D-dimers, fibrinogen, plasminogen activator inhibitor type 1 (PAI-1), fibronectin, CRP and IL-6 significantly exceeded the upper limit of the reference values. After 10 days of TPN, we detected significant differences in inflammatory state and hemostasis. Immunological state and hemostasis varied depending on the type of fat emulsion administered. The most likely reasons are the 2-fold higher concentrations of PUFAs in LCTs relative to MCTs/LCTs and a deficiency of LC in skeletal muscles. Both of these factors may contribute to the observed increase in the rate of eicosanoid synthesis.

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Heparin-like glycosaminoglycan is a receptor for Antithrombin III-dependent but not for thrombin-dependent prostacyclin production in human endothelial cells

Cited by 124 publications

References 24 publications

Antithrombin prevents endotoxin-induced hypotension by inhibiting the induction of nitric oxide synthase in rats

Antithrombin prevents endotoxin-induced hypotension by inhibiting the induction of nitric oxide synthase in rats

Influence of Antithrombin III on Coagulation and Inflammation in Porcine Septic Shock

L-carnitine and cancer cachexia. II. Effects of lipid emulsion used in total parenteral nutrition on parameters of hemostasis and inflammatory state in L-carnitine deficiency in myocytes

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