HMG-CoA reductase inhibitor induces a transient activation of high affinity nerve growth factor receptor, Trk, and morphological differentiation with fatal outcome in PC12 cells

Kumano, Takanori; Mutoh, Tatsuro; Nakagawa, Hiroto; Kuriyama, Masaru

doi:10.1016/s0006-8993(99)02469-5

Cited by 19 publications

(15 citation statements)

References 19 publications

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“…Notably, the human fetal OPCs responded to simvastatin treatment at substantially lower doses than the corresponding rat cells. Consistent with the effect on OPC process extension, short-term lipophilic statin treatment has also been shown to induce process extension in a neuronal cell line (Kumano et al, 2000) and in rodent mixed glial cultures (Paintlia et al, 2005). We found that such process extension could be replicated using another lipophilic statin, lovastatin, and could not be reproduced with the hydrophilic pravastatin.…”

Section: Effects Of Simvastatin On Opcs Early Effects Of Simvastatin supporting

confidence: 73%

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Simvastatin regulates oligodendroglial process dynamics and survival

Miron

Rajasekharan

Jarjour

et al. 2006

Glia

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Simvastatin, a lipophilic statin that crosses the blood-brain barrier, is being evaluated as a potential therapy for multiple sclerosis (MS) due to its anti-inflammatory properties. We assessed the effects of simvastatin on cultures of rat newborn and human fetal oligodendrocyte progenitor cells (OPCs) and human adult mature oligodendrocytes (OLGs) with respect to cellular events pertaining to myelin maintenance and repair. Short-term simvastatin treatment of OPCs (1 day) induced robust process extension, enhanced differentiation to a mature phenotype, and decreased spontaneous migration. These effects were reversed by isoprenoid products and mimicked with an inhibitor of Rho kinase (ROCK), the downstream effector of the isoprenylated protein RhoA GTPase. Prolonged treatment (2 days) caused process retraction that was rescued by cholesterol, and increased cell death (4 days) partially rescued by either cholesterol or isoprenoid co-treatment. In comparison, simvastatin treatment of human mature OLGs required a longer initial time course (2 days) to induce significant process outgrowth, mimicked by inhibiting ROCK. Prolonged treatment of mature OLGs was associated with process retraction (6 days) and increased cell death (8 days). Human-derived OPCs and mature OLGs demonstrated an increased sensitivity to simvastatin relative to the rodent cells, responding to nanomolar versus micromolar concentrations. Our findings indicate the importance of considering the short- and long-term effects of systemic immunomodulatory therapies on neural cells affected by the MS disease process. (c) 2006 Wiley-Liss, Inc.

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Section: Effects Of Simvastatin On Opcs Early Effects Of Simvastatin supporting

confidence: 73%

“…Simvastatin treatment at high concentrations for 2 days can inhibit neurite outgrowth (Kumano et al, 2000). The delayed process retraction we observed was rescued at least in part by application of mevalonate or cholesterol, but not isoprenoids, and was not reproduced using the ROCK inhibitor.…”

Section: Late Effects Of Simvastatin On Opcsmentioning

confidence: 71%

Simvastatin regulates oligodendroglial process dynamics and survival

Miron

Rajasekharan

Jarjour

et al. 2006

Glia

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“…As shown in figure 1A, lovastatin acid and pravastatin did not inhibit NO production at concentrations of up to 300 ÌM. Since statins have been reported to cause cell toxicity at higher concentrations [38,52,70], we were interested to know whether their inhibitory effect on NO generation is associated with this action. Using the 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) assay as an index for mitochondria function, we found that incubation with these statins at 30 ÌM for 40 h induced no significant cell toxicity.…”

Section: Statins Inhibit Inos/no Induction By Lps and Ifn-ámentioning

confidence: 99%

HMG-CoA Reductase Inhibitors Inhibit Inducible Nitric Oxide Synthase Gene Expression in Macrophages

Huang

Chen

et al. 2003

J Biomed Sci

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The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, statins, are potent inhibitors of cholesterol synthesis and have wide therapeutic use in cardiovascular diseases. Recent evidence, however, suggests that the beneficial effects of statins may extend beyond their action on serum cholesterol levels. In this study, we investigated the effects of lovastatin, pravastatin, atorvastatin and fluvastatin on macrophage formation of nitric oxide (NO) in murine RAW 264.7 cells. Stimulation of macrophages with lipopolysaccharide (LPS) and interferon-γ (IFN-γ) resulted in inducible NO synthase (iNOS) expression, which was accompanied by a large amount of NO formation. At concentrations of 0.1–30 µM, statins can inhibit stimuli-induced NO formation and iNOS induction to different extents. This inhibition occurs at the transcriptional level, and displays potency in the order of lovastatin > atorvastatin > fluvastatin >> pravastatin. We found that LPS-induced IĸB kinase and nuclear factor-ĸB (NF-ĸB) activation, as well as IFN-γ-induced signal transducer and activator of transcription 1 (STAT1) phosphorylation, were reduced by lovastatin. Moreover, inhibition by lovastatin of NO production and ĸB activation was reversed by mevalonate, geranylgeranyl pyrophosphate and farnesyl pyrophosphate. All these results suggest that inhibition of iNOS gene expression by statins can be attributed to interference with protein isoprenylation, which mediates both NF-ĸB and STAT1 activation in the upstream signaling pathways for iNOS gene transcription.

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“…In line with the documented, cell type-dependent role of small GTPases in cellular differentiation, HMG-CoA reductase inhibition has been shown to trigger phenotypic maturation of muscle [53], endothelial [54,55] and osteoblast [56][57][58] progenitors as well as neoplastic cells [56,[59][60][61][62][63][64][65][66][67]; while arresting adipocyte [58], myofibroblast [68], monocyte-to-osteoclast [69] and monocyte-to-macrophage [70,71] differentiation. Crucially, the maturational changes triggered by statin treatment are both morphological and functional.…”

Section: Effect Of Statins On Cellular Differentiationmentioning

confidence: 97%

Threes Company: Regulation of Cell Fate by Statins

Vamvakopoulos¹

2005

CDTCHD

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Inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (statins), the rate-limiting enzyme of the mevalonate biosynthetic pathway, are currently the leading prescription drugs worldwide. Programmed cell death (apoptosis) is a powerful physiological regulator of cellular development, function and dynamics. Statins are known to induce cellular apoptosis in vitro; however, the clinical relevance of this action remains controversial. This paper draws from 15 years' worth of research to explore the impact of statin treatment on cell fate, as represented by the interlinked processes of cellular growth, differentiation and apoptosis. In particular, I outline our current understanding of the pertinent molecular mechanisms; and discuss the evidence for clinical relevance of statin-induced apoptosis.

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HMG-CoA reductase inhibitor induces a transient activation of high affinity nerve growth factor receptor, Trk, and morphological differentiation with fatal outcome in PC12 cells

Cited by 19 publications

References 19 publications

Simvastatin regulates oligodendroglial process dynamics and survival

Simvastatin regulates oligodendroglial process dynamics and survival

HMG-CoA Reductase Inhibitors Inhibit Inducible Nitric Oxide Synthase Gene Expression in Macrophages

Threes Company: Regulation of Cell Fate by Statins

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