Cerivastatin ameliorates high insulin-enhanced neutrophil–endothelial cell adhesion and endothelial intercellular adhesion molecule-1 expression by inhibiting mitogen-activated protein kinase activation

Okouchi, Masahiro; Okayama, Naotsuka; Omi, Hitoshi; Imaeda, Kazuo; Shimizu, Manabu; Fukutomi, Tatsuya; Itoh, Makoto

doi:10.1016/s1056-8727(02)00245-3

Cited by 22 publications

(11 citation statements)

References 28 publications

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“…Statins have been reported to modulate various signaling molecules, including RhoA/ROCK, MAPK, and Akt . RhoA plays an important role in inflammatory and fibrotic responses .…”

Section: Discussionmentioning

confidence: 99%

Simvastatin inhibits transforming growth factor‐β1‐induced expression of type I collagen, CTGF, and α‐SMA in keloid fibroblasts

Mun

Kim

et al. 2013

Wound Repair Regeneration

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Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitor, is used to reduce cholesterol levels. Accumulating evidence has revealed the immunomodulatory and anti-inflammatory effects of simvastatin that prevent cardiovascular diseases. In addition, the beneficial effects of statins on fibrosis of various organs have been reported. However, the functional effect of statins on dermal fibrosis of keloids has not yet been explored. The objective of this study was to determine whether simvastatin could affect dermal fibrosis associated with keloids. We examined the effect of simvastatin on transforming growth factor (TGF)-β1-induced production of type I collagen, connective tissue growth factor (CTGF or CCN2), and α-smooth muscle actin (α-SMA). Keloid fibroblasts were cultured and exposed to different concentrations of simvastatin in the presence of TGF-β1, and the effects of simvastatin on TGF-β1-induced collagen and CTGF production in keloid fibroblasts were determined. The type I collagen, CTGF, and α-SMA expression levels and the Smad2 and Smad3 phosphorylation levels were assessed by Western blotting. The effect of simvastatin on cell viability was evaluated by assessing the colorimetric conversion of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide. Simvastatin suppressed TGF-β1-induced type I collagen, CTGF, and α-SMA production in a concentration-dependent manner. The TGF-β1-induced Smad2 and Smad3 phosphorylation levels were abrogated by simvastatin pretreatment. The inhibition of type I collagen, CTGF, and α-SMA expression by simvastatin was reversed by geranylgeranyl pyrophosphate, suggesting that the simvastatin-induced cellular responses were due to inhibition of small GTPase Rho involvement. A RhoA activation assay showed that preincubation with simvastatin significantly blocked TGF-β1-induced RhoA activation. The Rho-associated coiled kinase inhibitor Y27632 abrogated TGF-β1-induced production of type I collagen, CTGF, and α-SMA. However, Y27632 had no significant effect on TGF-β1-induced phosphorylation of Smad2 and Smad3. In conclusion, the present study suggests that simvastatin is an effective inhibitor of TGF-β1-induced type I collagen, CTGF, and α-SMA production in keloid fibroblasts.

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“…Statins have been reported to modulate various signaling molecules, including RhoA/ROCK, MAPK, and Akt . RhoA plays an important role in inflammatory and fibrotic responses .…”

Section: Discussionmentioning

confidence: 99%

Simvastatin inhibits transforming growth factor‐β1‐induced expression of type I collagen, CTGF, and α‐SMA in keloid fibroblasts

Mun

Kim

et al. 2013

Wound Repair Regeneration

View full text Add to dashboard Cite

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“…Although a number of reports have discussed the pleiotropic effects of simvastatin, the underlying mechanisms by which simvastatin regulates inflammation and fibrotic processes have not been elucidated. Statin‐sensitive signalling molecules include Rho, mitogen‐activated protein kinase and Akt 50–52 . RhoA plays an important role in the inflammatory and fibrotic response 22,53 .…”

Section: Discussionmentioning

confidence: 99%

Simvastatin attenuates experimental small airway remodelling in rats

Ou¹,

Wen

Uhal

et al. 2009

Respirology

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Simvastatin attenuated experimental small airway remodelling, as indicated by decreases in collagen deposition and small airway wall thickening. Simvastatin may inhibit cigarette smoke-induced small airway remodelling by reducing growth factor expression and inflammation. The mechanism of action of simvastatin on small airway remodelling involved RhoA and the Smad signalling pathway. These findings indicate that simvastatin may have potential beneficial effects in the treatment of COPD.

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“…Notably, we also observed that simvastatin given 2 h after BDL induction reduced serum activities of ALT and AST by more than 70% as well as hepatic levels of MPO and KC by more than 38%, suggesting also a therapeutic potential of simvastatin in conditions with obstructed bile flow. Although the signalling mechanisms downstream of HMG‐CoA reductase activity were not examined in this study, it is of interest to mention that statin‐sensitive signalling molecules include Rho guanosine triphosphatases and mitogen‐activated protein kinases (Okouchi et al. , 2003; Patel and Corbett, 2003), and most anti‐inflammatory actions of statins have been ascribed to reduced prenylation of Rho guanosine triphosphatases (Laufs and Liao, 2003).…”

Section: Discussionmentioning

confidence: 99%

Simvastatin protects against cholestasis‐induced liver injury

Dold

Laschke

Lavasani

et al. 2009

British J Pharmacology

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Background: Bile duct obstruction is associated with hepatic accumulation of leukocytes and liver injury. The aim of this study was to evaluate the effect of simvastatin on cholestasis-induced liver inflammation and tissue damage. Experimental approach: C57BL/6 mice were treated with simvastatin (0.02 and 0.2 mg·kg -1 ) and vehicle before and after undergoing bile duct ligation (BDL) for 12 h. Leukocyte recruitment and microvascular perfusion in the liver were analysed using intravital fluorescence microscopy. CXC chemokines in the liver were determined by enzyme-linked immunosorbent assay. Liver damage was monitored by measuring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Hepatic levels of myeloperoxidase (MPO) were also determined. Key results: Administration of 0.2 mg·kg -1 simvastatin decreased ALT and AST by 87% and 83%, respectively, in BDL mice. This dose of simvastatin reduced hepatic formation of CXC chemokines by 37-82% and restored sinusoidal perfusion in cholestatic animals. Moreover, BDL-induced leukocyte adhesion in sinusoids and postsinusoidal venules, as well as MPO levels in the liver, was significantly reduced by simvastatin. Notably, administration of 0.2 mg·kg -1 simvastatin 2 h after BDL induction also decreased cholestatic liver injury and inflammation. Conclusions and implications:These findings show that simvastatin protects against BDL-induced liver injury. The hepatoprotective effect of simvastatin is mediated, at least in part, by reduced formation of CXC chemokines and leukocyte recruitment. Thus, our novel data suggest that the use of statins may be an effective strategy to protect against the hepatic injury associated with obstructive jaundice.

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Cerivastatin ameliorates high insulin-enhanced neutrophil–endothelial cell adhesion and endothelial intercellular adhesion molecule-1 expression by inhibiting mitogen-activated protein kinase activation

Cited by 22 publications

References 28 publications

Simvastatin inhibits transforming growth factor‐β1‐induced expression of type I collagen, CTGF, and α‐SMA in keloid fibroblasts

Simvastatin inhibits transforming growth factor‐β1‐induced expression of type I collagen, CTGF, and α‐SMA in keloid fibroblasts

Simvastatin attenuates experimental small airway remodelling in rats

Simvastatin protects against cholestasis‐induced liver injury

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