Inhibition of pancreatic stellate cell activation by the hydroxymethylglutaryl coenzyme A reductase inhibitor lovastatin

Jaster, Robert; Brock, Peter; Sparmann, Gisela; Emmrich, Jörg; Liebe, Stefan

doi:10.1016/s0006-2952(03)00075-3

Cited by 33 publications

(22 citation statements)

References 44 publications

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“…In a recent study, Masamune et al (2006) have demonstrated that curcumin, the yellow pigment in curry, inhibits PSC proliferation. Furthermore, other groups provided evidence that compounds like statins, taurine, or the green tea extract epigallocatechin gallate could also block the proliferation of PSCs in experimental in vitro or in vivo models, but the exact cellular mechanisms are still not fully understood (Jaster et al, 2003;Asaumi et al, 2006;Shirahige et al, 2007). Note that all of these mentioned substances are potent inducers of the cytoprotective enzyme HO-1 in several cell types, but no information is available concerning their effects on HO-1 in the pancreas (Olszanecki and Marcinkiewicz, 2004;Wu et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-1 Inhibits the Proliferation of Pancreatic Stellate Cells by Repression of the Extracellular Signal-Regulated Kinase1/2 Pathway

Schwer¹,

Guerrero²,

Humar³

et al. 2008

J Pharmacol Exp Ther

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Activation of pancreatic stellate cells (PSCs) is the key process in the development of pancreatic fibrosis, a common feature of chronic pancreatitis and pancreatic cancer. In recent studies, curcumin has been shown to inhibit PSC proliferation via an extracellular signal-regulated kinase (ERK)1/2-dependent mechanism. In addition, curcumin is a potent inducer of the cytoprotective enzyme heme oxygenase-1 (HO-1) in other cell types. Therefore, the aims of this study were to 1) characterize the effect of curcumin on HO-1 gene expression in PSCs, 2) explore whether HO-1 induction contributes to the inhibitory effect of curcumin on PSC proliferation, and 3) clarify the involvement of the mitogen-activated protein kinase (MAPK) family in this context. Cultured rat PSCs were incubated with curcumin and assessed for HO-1 up-regulation by Northern blot analysis, immunoblotting, and activity assays. The effect of HO-1 on platelet-derived growth factor (PDGF)-induced PSC proliferation and MAPK activation was determined by immunoblotting, cell proliferation assays, and cell count analyses. Curcumin induced HO-1 gene expression in PSCs in a timeand dose-dependent manner and inhibited PDGF-mediated ERK1/2 phosphorylation and PSC proliferation. These effects were blocked by treatment of PSCs with tin protoporphyrin IX, an HO inhibitor, or transfection of HO-1 small interfering RNA. Our data provide evidence that HO-1 induction contributes to the inhibitory effect of curcumin on PSC proliferation. Therefore, therapeutic up-regulation of HO-1 could represent a mode for inhibition of PSC proliferation and thus may provide a novel strategy in the prevention of pancreatic fibrosis.Pancreatic fibrosis is a common histopathological feature in chronic pancreatitis and pancreatic cancer. It is now generally accepted that pancreatic stellate cells (PSCs) play a crucial role in the fibrogenic process (Omary et al., 2007). In response to profibrogenic stimuli, PSCs undergo transdifferentiation from quiescent phenotypes into highly proliferative myofibroblast-like cells, which express the cytoskeletal protein ␣-smooth muscle actin and synthesize increased amounts of extracellular matrix components (Apte et al., 1998;Bachem et al., 1998). Recent studies have identified platelet-derived growth factor (PDGF)-BB as the most potent mitogen for pancreatic stellate cells in culture, and its effects have been extensively studied (Apte et al., 1998;Luttenberger et al., 2000). PDGF stimulates PSC cell proliferation by activating key effectors, including ras, raf, and the extracellular signal-regulated kinase (ERK)1/2 cascade (Jaster et al., 2002;Masamune et al., 2003a). Data from recent studies suggest that p38 mitogenactivated protein kinase (MAPK) and c-Jun NH 2 -terminal kinase (JNK) signaling pathways might also play a role in PSC proliferation ((Masamune et al., 2003b((Masamune et al., , 2004. Thus, modulation of MAPK activation is considered a potential strategy to inhibit PSC growth.Heme oxygenases (HOs) are the rate-limiting enzymes...

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Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-1 Inhibits the Proliferation of Pancreatic Stellate Cells by Repression of the Extracellular Signal-Regulated Kinase1/2 Pathway

Schwer¹,

Guerrero²,

Humar³

et al. 2008

J Pharmacol Exp Ther

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“…These cells likewise undergo culture-induced transdifferentiation (Jaster et al 2003b). Activated pancreatic stellate cells similarly contribute to pancreatic fibrosis and the development of chronic pancreatitis and pancreatic cancer (Jaster et al 2003a).…”

Section: Introductionmentioning

confidence: 99%

Transdifferentiation of vocal-fold stellate cells and all-trans retinol-induced deactivation

2005

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The maculae flavae of the human vocal folds include dense extracellular matrices and compacted cells with a stellate morphology. These vocal-fold stellate cells are thought to participate in the metabolism of extracellular matrices essential in maintaining vocal-fold viscoelasticity required for phonation. We have isolated and cultured these new cells and have tested the hypothesis that they maintain a distinct cellular and biochemical phenotype. We have compared proliferation rates, changes on immunophenotype, and intracellular lipid and vitamin A storage. Vocal-fold stellate cells undergo culture-induced transdifferentiation to a myofibroblast-like phenotype with an altered phenotype resembling, but not identical to, activated hepatic and pancreatic stellate cells. Our results reveal that these cells are capable of responding to exogenous all-trans retinol in culture. Exposure to this synthetic co-factor causes deactivation characterized by decreased proliferation, loss of the activated stellate cell marker, alpha-smooth muscle actin, and restoration of intracellular lipid and vitamin A metabolite storage. These data establish a new and distinct cellular target for future investigations of the viscoelastic properties of the vocal-fold mucosa during normal phonation, aging, vocal-fold scarring, laryngeal fibrosis, and myofibroblastoma.

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“…39 Taken together, our results suggest that treatment with pravastatin prevented the progression of pancreatic inflammation and fibrosis by reducing activation of PSCs through its anti-oxidative effect. Previous experimental studies in vitro 40,41 have shown that statins inhibit activation of fibroblasts and reduce expression of CTGF from fibroblasts through the interruption of Ras signaling and suppression of translocation of RhoA to cellular membrane. These observations suggest that statins also exert direct beneficial actions on PSCs.…”

Section: Pravastatin Attenuates Chronic Pancreatitis L Wei Et Almentioning

confidence: 99%

Treatment with pravastatin attenuates progression of chronic pancreatitis in rat

Wei

Yamamoto

Harada

et al. 2011

Laboratory Investigation

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As appropriate therapies for pancreatic fibrosis and inflammation are limited, prognosis of chronic pancreatitis has not improved to date. Recent studies have shown that statins improve inflammation and fibrosis in several organs. We therefore examined the therapeutic effect of pravastatin on progression of chronic pancreatitis by starting this treatment after induction of pancreatic fibrosis in rats. Chronic pancreatitis was induced by continuous pancreatic ductal hypertension (PDH) for 14 days according to our previous study. Pravastatin at a dose of 10 mg/kg/day was administrated directly into the duodenum via cannula from 2 days after induction of PDH. Progression of pancreatic fibrosis and expression levels of transforming growth factor-b1 and tumor necrosis factor-a mRNA were markedly attenuated after commencement of pravastatin compared with untreated group with PDH. In addition, pravastatin treatment markedly improved pancreatic exocrine function and significantly elevated expression level of interleukin (IL)-10 and superoxide dismutase activity in the pancreas compared with the untreated group with PDH. These results revealed that pravastatin substantially attenuates the progression of pancreatic inflammation, fibrosis and exocrine dysfunction probably by its anti-oxidative property and overproduction of IL-10 in animal model of chronic pancreatitis. These results provide an experimental evidence that pravastatin exerts beneficial effect for progression of chronic pancreatitis.

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Inhibition of pancreatic stellate cell activation by the hydroxymethylglutaryl coenzyme A reductase inhibitor lovastatin

Cited by 33 publications

References 44 publications

Heme Oxygenase-1 Inhibits the Proliferation of Pancreatic Stellate Cells by Repression of the Extracellular Signal-Regulated Kinase1/2 Pathway

Heme Oxygenase-1 Inhibits the Proliferation of Pancreatic Stellate Cells by Repression of the Extracellular Signal-Regulated Kinase1/2 Pathway

Transdifferentiation of vocal-fold stellate cells and all-trans retinol-induced deactivation

Treatment with pravastatin attenuates progression of chronic pancreatitis in rat

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