Effect of HMG-CoA reductase inhibitors on proliferation and protein synthesis by rat hepatic stellate cells

Rombouts, Krista; Kisanga, Elton R.; Hellemans, Karine; Wielant, Annemie; Schuppan, Detlef; Geerts, Albert

doi:10.1016/s0168-8278(03)00051-5

Cited by 75 publications

(72 citation statements)

References 62 publications

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“…Statins have been shown in in vitro models of these fibrotic disorders to inhibit the proliferation of cells involved in the fibrotic process causing their increased apoptosis, as well as, causing a decrease in their production of extracellular matrix components. These results suggest that statins may also have a beneficial effect in various fibroproliferative disorders (56)(57)(58).…”

Section: (49)mentioning

confidence: 76%

Statins and the vasculopathy of systemic sclerosis: Potential therapeutic agents?

Derk

Jimenez

2006

Autoimmunity Reviews

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Section: (49)mentioning

confidence: 76%

Statins and the vasculopathy of systemic sclerosis: Potential therapeutic agents?

Derk

Jimenez

2006

Autoimmunity Reviews

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“…2,4,5 In vitro-activated HSC have also been demonstrated to change their morphology with loss of lipid droplets and increased expression of a-SMA. [32][33][34] In our previous study, prophylactic treatment starting directly after the BDL resulted in a lower number of MFB in the liver and less collagen accumulation, but without significant decrease in cytokine production or inflammation. 8 If atorvastatin was administrated later, but still before established fibrosis, collagen formation was reduced.…”

Section: Discussionmentioning

confidence: 87%

Atorvastatin inhibits proliferation and apoptosis, but induces senescence in hepatic myofibroblasts and thereby attenuates hepatic fibrosis in rats

Klein

Klösel

Schierwagen

et al. 2012

Laboratory Investigation

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Hepatic myofibroblasts (MFB) show increased proliferation, migration and collagen production, which are crucial for hepatic fibrogenesis. Atorvastatin treatment inhibits proliferation, apoptosis and cytokine production of MFB in bile ductligated (BDL) rats in vivo. Here, we have further investigated the underlying mechanisms. Primary rat hepatic stellate cells (HSC) were isolated and culture-activated to hepatic MFB. Following 3 days of incubation with atorvastatin (10 À 4 , 10 À 5 and 10 À 6 M), transcription levels of profibrotic cytokines (transforming growth factor-b1, connective tissue growth factor and TIMP1) and procollagen Ia were analyzed by real time PCR. Proliferation was investigated by 5'-bromo-2'-deoxyuridine assays. a-Smooth muscle actin protein expression was examined by western blotting. Fluorescence-activated cell sorting analysis of Annexin V and propidium iodide were used to measure apoptosis. Furthermore, p21 western blotting and b-galactosidase staining were investigated in MFB as senescence markers. Subsequently, hepatic expression of desmin and senescence markers were analyzed in the livers of rats receiving atorvastatin (15 mg/kg*d) for 1 week starting 3 and 5 weeks after BDL. Atorvastatin inhibited the activation of HSC to MFB and decreased cytokine and collagen production in MFB in vitro. In addition, proliferation, cytokine and collagen production of MFB were reduced by atorvastatin. Atorvastatin initiated apoptosis at 10 À 4 M and attenuated it at 10 À 5 M. Atorvastatin induced p21 protein expression and b-galactosidase staining of MFB in vitro and in vivo. Atorvastatin elicits similiar effects on MFB as previously seen in vivo: it decreases MFB turnover and fibrogenesis. We suggest that a further mechanism explaining these effects is senescence of cells.

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“…Therefore, this drug also has potential "offtarget" actions that might influence the cellular response to PDGF-BB. Nevertheless, the novel evidence that AY9944 inhibits HSC growth raises the intriguing possibility that statins, which have also been reported to inhibit HSC activation [62], might also function by down-regulating Hh signaling.…”

Section: Discussionmentioning

confidence: 99%

Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells

Yang

Wang

Mao

et al. 2008

Journal of Hepatology

185

203

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show abstract

Effect of HMG-CoA reductase inhibitors on proliferation and protein synthesis by rat hepatic stellate cells

Cited by 75 publications

References 62 publications

Statins and the vasculopathy of systemic sclerosis: Potential therapeutic agents?

Statins and the vasculopathy of systemic sclerosis: Potential therapeutic agents?

Atorvastatin inhibits proliferation and apoptosis, but induces senescence in hepatic myofibroblasts and thereby attenuates hepatic fibrosis in rats

Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells

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