Atorvastatin neutralises the thrombin-induced tissue factor expresion in endothelial cells via geranylgeranyl pyrophosphate

Martínez‐Sales, Vicenta; Vila, Virtudes; Ferrando, M.; Regañón, Edelmiro

doi:10.1007/s10616-010-9319-4

Cited by 6 publications

(3 citation statements)

References 13 publications

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“…Statins have been found to diminish procoagulant activity by influencing different stages of the coagulation cascade such as upregulating tissue-type plasminogen activator (t-PA) 29 and suppressing tissue factor. 21 The effects of statins on balance between t-PA and PAI-1 expression in hyperglycemia and the kinetic mechanism remain to be investigated in our future studies. Considering that the pleiotropic effects of statins are more than the inhibitive effect of RhoA, statins may be superior to the RhoA kinase inhibitors fasudil and hydroxyfasudil, which are widely used in the clinic now.…”

Section: Discussionmentioning

confidence: 96%

“…Endothelial PAI-1 production can be induced by numerous factors such as tumor necrosis factor α, 20 thrombin, 21 angio-tensin II, 22 transforming growth factor, 23 etc. Increased PAI-1 production induced by high glucose was previously observed in human umbilical vein endothelial cells (HUVECs), 24 bovine aortic endothelial cells (BAECs) 25 and human saphenous vein endothelial cells (HSVECs).…”

Section: Discussionmentioning

confidence: 99%

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Statins suppress glucose-induced plasminogen activator inhibitor-1 expression by regulating RhoA and nuclear factor-kB activities in cardiac microvascular endothelial cells

Zhu²,

Yao³

et al. 2013

Exp Biol Med (Maywood)

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The aim of this study was to investigate the possible proinflammatory signaling pathways involved in statin inhibition of glucose-induced plasminogen activator inhibitor-1 (PAI-1) expression in cardiac microvascular endothelial cells (CMECs). Primary rat CMECs were grown in the presence of 5.7 or 23 mmol/L glucose. PAI-1 mRNA and protein expression levels were measured by realtime polymerase chain reaction, Western blotting and enzyme-linked immunosorbent assay, respectively. A pull-down assay was performed to determine RhoA activity. IκBα protein expression was measured by Western blotting, nuclear factor (NF)-κB activation was detected by electrophoretic mobility shift assay and its transcription activity was determined by a dual luciferase reporter gene assay. PAI-1 mRNA and protein expression levels were both increased with high glucose concentrations, but they were significantly suppressed by simvastatin and atorvastatin treatment (P < 0.01) and the effects were reversed by mevalonate (100 μmol/L) and geranylgeranyl pyrophosphate (10 μmol/L) but not farnesyl pyrophosphate (10 μmol/L). Such effects were similar to those of a RhoA inhibitor, C3 exoenzyme (5 μg/mL), inhibitors of RhoA kinase (ROCK), Y-27632 (10 μmol/L) and hydroxyfasudil (10 μmol/L) and an NF-κB inhibitor, BAY 11-7082 (5 μmol/L). High glucose-induced RhoA and NF-κB activations in CMECs were both significantly inhibited by statins (P < 0.01). Simvastatin and atorvastatin equally suppress high glucose-induced PAI-1 expression. These effects of statins may occur partly by regulating the RhoA/ROCK-NF-κB pathway. The multifunctional roles of statins may be particularly beneficial for patients with metabolic syndrome.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Statins suppress glucose-induced plasminogen activator inhibitor-1 expression by regulating RhoA and nuclear factor-kB activities in cardiac microvascular endothelial cells

Zhu²,

Yao³

et al. 2013

Exp Biol Med (Maywood)

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“…Sodium ferulate (SF) is such a drug. It decreases cholesterol synthesis by inhibiting mevalonate 5-pyrophosphate dehydrogenase, an action that prevents the conversion of mevalonite to GGPP and the subsequent activation of the RhoA/Rho-kinase pathway ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

Sodium ferulate lowers portal pressure in rats with secondary biliary cirrhosis through the RhoA/Rho-kinase signaling pathway: A preliminary study

Wei

Yang²,

Wang

et al. 2014

International Journal of Molecular Medicine

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Cirrhotic rats show higher expression levels of hepatic RhoA and Rho-kinase than normal healthy rats, and the activation of this signaling pathway leads to portal hypertension. Sodium ferulate (SF) has been shown to decrease the production of geranylgeranyl pyrophosphate (GGPP), a substance essential for RhoA activation. In the present study, to investigate the effects of SF on fibrosis, portal hypertension and the RhoA/Rho-kinase pathway, hepatic cirrhosis was induced in rats by bile duct ligation. Liver function and fibrogenesis-related biochemical parameters, the hepatic hydroxyproline content, the pathological characteristics of the liver sections and the levels of hepatic α-smooth muscle actin (α-SMA; by immunohistochemistry) were analyzed to assess effects of SF on hepatic fibrosis. In addition, hepatic RhoA, Rho-kinase and endothelial nitric oxide synthase (eNOS) expression was examined by immunohistochemistry. Apoptosis in the SF-treated and SF + GGPP-treated rat primary hepatic stellate cells (HSCs) and a human stellate cell line (LX-2) was examined by flow cytometry. Intrahepatic resistance and responsiveness to the α1-adrenoceptor agonist, methoxamine, were investigated by in situ liver perfusion. Treatment with SF did not affect fibrosis-related biochemical parameters or the hydroxyproline content; however, SF reduced the histological evidence of fibrosis and hepatocyte damage. The SF-treated rats had a significantly lower expression of α-SMA and Rho-kinase, as well as an increased hepatic eNOS content; however, SF did not affect RhoA expression. The SF-treated HSCs had a significantly increased apoptotic rate compared to the untreated rats. Following the addition of GGPP, the rate apoptotic rate decreased. SF reduced basal intrahepatic resistance and the responsiveness of hepatic vascular smooth muscle to methoxamine. Therefore, our data demonstrate that SF reduces fibrogenesis, decreases portal pressure in cirrhotic rats and inhibits the activation of the RhoA/Rho-kinase signaling pathway.

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Tissue Factor

Sergeeva¹

2016

Encyclopedia of Signaling Molecules

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Atorvastatin neutralises the thrombin-induced tissue factor expresion in endothelial cells via geranylgeranyl pyrophosphate

Cited by 6 publications

References 13 publications

Statins suppress glucose-induced plasminogen activator inhibitor-1 expression by regulating RhoA and nuclear factor-kB activities in cardiac microvascular endothelial cells

Statins suppress glucose-induced plasminogen activator inhibitor-1 expression by regulating RhoA and nuclear factor-kB activities in cardiac microvascular endothelial cells

Sodium ferulate lowers portal pressure in rats with secondary biliary cirrhosis through the RhoA/Rho-kinase signaling pathway: A preliminary study

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