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PubMed1997

Effects of simvastatin on the metabolism of polyunsaturated fatty acids and on glycerolipid, cholesterol, and de novo lipid synthesis in THP-1 cells.

In the monocytic THP-1 cells, the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor simvastatin (5 microM) enhances the conversion of exogenous linoleic (18:2 n-6) and eicosapentaenoic (20:5 n-3) acids to their long-chain polyunsaturated fatty acid (LC-PUFA) derivatives, and this effect is associated with changes in the desaturation steps. In addition, formation of monounsaturated fatty acids from endogenously synthesized precursors is increased. These metabolic changes lead to elevated LC-PUFA and fatty acid (FA) unsaturation in cells. The effects of simvastatin on FA metabolism are associated with increased synthesis of triglycerides from glycerol. The dose-effect relationships for the activity of simvastatin on total linoleic acid (LA) conversion and cholesterol synthesis reveal that enhancement of PUFA metabolism is already maximal at 0.5 microM simvastatin, whereas cholesterol synthesis is further inhibited by concentrations of simvastatin up to 5 microM. The effects of 5 microM simvastatin on PUFA metabolism are partially prevented by mevalonate (1 mM) and geranylgeraniol (5 microM) but not by farnesol (10 microM). These data indicate that HMG-CoA inhibitors have profound effects on PUFA metabolism, and that the pathways for cholesterol and PUFA synthesis are mutually modulated.

Acetates↗
PubMed1996

Separate compartments for the production of sterols, carotenoids and gibberellins in Gibberella fujikuroi.

Substrate flows in the sterol, carotenoid and gibberellin pathways of Gibberella fujikuroi were examined by isotope-dilution experiments. The wild type and two carotenoid mutants of this fungus were grown in minimal medium with abundant glucose, limiting ammonium nitrate and a radioactively labelled precursor (either acetate, mevalonate or leucine). The precursors did not affect growth or terpenoid production, with two exceptions; leucine allowed additional growth, as expected from the nitrogen limitation in the medium, and mevalonate inhibited the accumulation of gibberellins, but only if added before the onset of gibberellin production. The relative contributions of glucose, mevalonate, leucine and acetate as terpenoid precursors, calculated from the specific radioactivities of ergosterol, neurosporaxanthin and phytoene, were different for different products and different precursors. We conclude that the biosyntheses of sterols, gibberellins and carotenoids in Gibberella are physically separated in different subcellular compartments with independent substrate pools. The same results were obtained with the three strains, except for carotenoid production, indicating that this pathway is regulated independently from other terpenoid pathways.

Acetates↗
PubMed2004

Paradoxical effects of statins on aortic valve myofibroblasts and osteoblasts: implications for end-stage valvular heart disease.

OBJECTIVES: We evaluated the effects of statins on aortic valve myofibroblasts (AVMFs) and osteoblast calcification in vitro. METHODS AND RESULTS: Cultured porcine AVMFs and M2-10B4 cells were treated with simvastatin and pravastatin. Mevalonate, a 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase metabolite, was added in parallel experiments. Manumycin A, which inhibits protein prenylation, was added to cultures in the absence of statins. Calcification was assessed by counting the number of calcific nodules formed and measuring alkaline phosphatase activity (APA). Statins inhibited calcific nodule formation (P<0.01) and APA (P<0.01) in AVMFs. Mevalonate reversed the statin effect on nodule formation (P<0.05) and APA (P<0.01). Manumycin A had no effect on either parameter. M2-10B4 cells treated with simvastatin formed more calcific nodules compared with controls (P<0.01), although pravastatin had no effect. Both statins, however, resulted in increased APA in M2-10B4 cells (P<0.01). Mevalonate had no impact on nodule numbers or APA in M2-10B4 cells. CONCLUSIONS: Statins inhibit calcification in AVMFs by inhibiting the cholesterol biosynthetic pathway, independent of protein prenylation, but paradoxically stimulate bone cell calcification. Because 15% of patients with end-stage valvular heart disease exhibit mature bone in their aortic valves, statins may differentially regulate calcification within a valve, limiting dystrophic calcification but promoting ossification of formed bone.

Animals↗
PubMed1999

Selective inhibition of formyl-methionyl-leucyl-phenylalanine (fMLF)-dependent superoxide generation in neutrophils by pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase.

It has been shown previously that inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, such as compactin, lovastatin, and pravastatin, block cholesterol synthesis, suppress lymphocyte functions, and beneficially affect atherogenesis. Recently, it was reported that compactin and lovastatin inhibit the respiratory burst of DMSO-differentiated HL-60 cells, an effect reversed by mevalonic acid. The mode of action of these inhibitors in this role is not understood fully. Thus, we studied the mechanism of inhibition of neutrophil superoxide (O2*-) generation by pravastatin and found that pravastatin at 0.5 mM inhibited the receptor-mediated tyrosine kinase (TK)-dependent pathway of O2*- generation and also luminol chemiluminescence but not the protein kinase C (PKC)-dependent or the TK- and PKC-independent pathways of O2*- generation in neutrophils. Pravastatin also inhibited the tumor necrosis factor-alpha- and formyl-methionyl-leucyl-phenylalanine-induced phosphorylation of a tyrosine of a 115-kDa protein. These effects were not reversed by mevalonate. From these results it is concluded that pravastatin inhibited receptor-mediated O2*-generation by decreasing tyrosine phosphorylation but not by inhibiting the formation of an intermediate in the biosynthesis of cholesterol.

Drug Interactions↗
PubMed2004

Fluvastatin prevents vascular hyperplasia by inhibiting phenotype modulation and proliferation through extracellular signal-regulated kinase 1 and 2 and p38 mitogen-activated protein kinase inactivation in organ-cultured artery.

OBJECTIVE: We examined the inhibitory mechanisms of fluvastatin on FBS-induced vascular hypertrophy assessed by organ-cultured rat tail artery. METHODS AND RESULTS: After 5 days of culture with 10% FBS, hyperplastic morphological changes in the media layer were induced. Treatment with 1 mumol/L fluvastatin significantly inhibited these changes. In the FBS-cultured arteries, the protein expression ratio of alpha-actin/beta-actin was significantly decreased, indicating the change to synthetic phenotype. Fluvastatin restored the decreased expression ratio, and the addition of mevalonate (100 mumol/L) suppressed this recovery. In accordance with the synthetic morphological changes, the absolute force of contractions induced by stimuli was decreased. Fluvastatin treatment also restored the decreased contractility, and the addition of mevalonate suppressed this recovery. In the arteries cultured with FBS, extracellular signal-regulated kinase 1 and 2 (ERK1/2) and p38 mitogen-activated protein kinase (p38MAPK) phosphorylation were significantly increased. Fluvastatin inhibited these phosphorylations, and mevalonate prevented the action of fluvastatin. CONCLUSIONS: These results suggest that fluvastatin inhibits vascular smooth muscle phenotype modulation to synthetic phenotype and proliferation by inhibiting the local metabolic pathway of cholesterol in smooth muscle cells, which inhibits hyperplastic changes in the vascular wall. The antihyperplastic actions by statins may be induced by inhibiting the ERK1/2 and p38MAPK activities, possibly through inhibition of prenylated Ras. We examined the inhibitory mechanisms of fluvastatin on FBS-induced vascular hypertrophy assessed by organ-cultured artery. Results suggest that fluvastatin inhibits vascular smooth muscle phenotype modulation and proliferation by inhibiting the ERK1/2 and p38MAPK activities through depletion of mevalonate in smooth muscle cells, resulting in inhibiting vascular hyperplastic changes.

Animals↗
PubMed2002

Cerivastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, inhibits cardiac myocyte hypertrophy induced by endothelin.

We investigated the direct effects of cerivastatin on hypertrophy of cultured rat neonatal myocytes induced by endothelin and the mechanism by which cerivastatin exerts its effects. Endothelin significantly increased [14C]phenylalanine ([14C]Phe) incorporation, atrial natriuretic peptide (ANP) release, ANP mRNA expression and cell size. Cerivastatin significantly reduced the increase in [14C]phenylalanine incorporation, ANP peptide release, ANP mRNA expression and cell size induced by endothelin, but pravastatin did not. Exogenous mevalonate completely prevented the inhibitory effect of cerivastatin on [14C]phenylalanine incorporation, ANP release and cell size. Cotreatment with geranylgeranyl pyrophosphate also attenuated the effect of cerivastatin on [14C]phenylalanine incorporation, but cotreatment with farnesyl pyrophosphate or squalene did not. Furthermore, both Rho inhibitor C3 exoenzyme and Rho-dependent kinase inhibitor, (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide.2HCl (Y27632) significantly decreased [14C]phenylalanine incorporation, ANP secretion, ANP mRNA expression and cell size. Cerivastatin decreased endothelin-induced Rho protein expression, and mevalonate and geranylgeranyl pyrophosphate reversed this effect. These results suggest that cerivastatin directly attenuates cardiac hypertrophy induced by endothelin in cultured rat myocytes partly by inhibition of the Rho pathway.

ADP Ribose Transferases↗
PubMed1984

Inhibition of hepatic cholesterol and triglyceride synthesis by guanabenz acetate.

Abundant evidence exists for the cumulative adverse effects of hypertension and hypercholesterolemia on the progression of coronary heart disease. The antihypertensive drug guanabenz acetate has been shown to lower serum cholesterol levels, but the mechanism for this effect is unclear. To explore this problem, suspensions of rat liver cells were incubated with guanabenz and labeled lipogenic precursors. Guanabenz produced an inhibition of cholesterol production from [14C]acetate that ranged from 10% at 0.005 mM guanabenz to 90% at 0.20 mM guanabenz. Inhibition of cholesterol production from [14C]mevalonate was half as great as inhibition from [14C]acetate. Thus, guanabenz inhibits hepatic cholesterol production at both pre- and postmevalonic sites in the sterol pathway. Synthesis of triglycerides from [14C]palmitate also was inhibited by guanabenz, whereas oxidation of [14C]palmitate to 14CO2 was stimulated. Therefore, the inhibition of triglyceride formation from fatty acid produced by guanabenz may be due to the stimulation of fatty acid oxidation. The clinical effects of guanabenz on serum lipid levels may relate to its direct actions on hepatic cholesterol and triglyceride biosynthesis.

Animals↗
PubMed2003

Epidermal growth factor receptor-targeted therapy potentiates lovastatin-induced apoptosis in head and neck squamous cell carcinoma cells.

PURPOSE: Mevalonate metabolites are vital for a variety of key cellular functions with the biosynthetic products including cholesterol and farnesyl and geranylgeranyl isoprenoids. Inhibition of this pathway using lovastatin induces a potent apoptotic response in a specific subset of human tumor-derived cell lines, including head and neck squamous cell carcinomas (HNSCC). In this study, we evaluated the potential of a number of chemotherapeutics that demonstrate activity in HNSCC, including an inhibitor of epidermal growth factor receptor (EGFR) to potentiate the cytotoxic effects of lovastatin. METHODS: We evaluated the cytotoxic effects of combining a variety of chemotherapeutics with lovastatin using the MTT assay and flow cytometry. The MCF-7 lovastatin-resistant breast adenocarcinoma cell line and the lovastatin-sensitive HNSCC cell lines SCC9 and SCC25 were tested. Expression levels of EGFR and ligand activated EGFR following lovastatin treatment were analyzed by Western blotting. RESULTS: Pretreatment or concomitant treatment of 10 microM lovastatin did not significantly augment the effects of a variety of chemotherapeutic agents tested in these cell lines. Co-administration with actinomycin D or cycloheximide, drugs that inhibit RNA and protein synthesis, respectively, inhibited lovastatin-induced apoptosis in these cell lines. This suggests a requirement for the cellular functions disrupted by these chemotherapeutic agents in lovastatin-induced apoptosis of HNSCC cells. In contrast to the chemotherapeutics analyzed, the AG1478 tyrosine kinase inhibitor of the EGFR demonstrated additive cytotoxic effects in combination with lovastatin in HNSCC cells. Mevalonate metabolites may regulate EGFR function, suggesting that lovastatin may inhibit the activity of this receptor. Indeed, lovastatin treatment inhibited EGF-induced autophosphorylation of the EGFR in the SCC9 and SCC25 cell lines. Pretreatment of SCC9 and SCC25 cell lines for 24 h with 10 microM lovastatin, conditions that demonstrated significant inhibition of EGF-induced EGFR autophosphorylation, induced significant additive effects in combination with AG1478. CONCLUSION: These results demonstrated the ability of EGFR pathway inhibitors to potentiate lovastatin-induced apoptosis and suggested that lovastatin may target the EGFR pathway in HNSCC cells.

Antineoplastic Agents↗
PubMed1998

v-K-ras leads to preferential farnesylation of p21(ras) in FRTL-5 cells: multiple interference with the isoprenoid pathway.

The isoprenoid pathway in FRTL-5 thyroid cells was found to be deeply altered on transformation with v-K-ras. A dramatic overall reduction of protein prenylation was found in v-K-ras-transformed cells in comparison with the parent FRTL-5 cells, as shown by labeling cells with [3H]mevalonic acid. This phenomenon was accompanied by a relative increase of p21(ras) farnesylation and by a decrease of the ratio between the amounts of geranylgeraniol and farnesol bound to prenylated proteins. Analysis of protein prenylation in FRTL-5 cells transformed by a temperature-sensitive mutant of the v-K-ras oncogene indicated that these variations represent an early and specific marker of active K-ras. Conversely, FRTL-5 cells transformed with Harvey-ras showed a pattern of [3H]-mevalonate (MVA)-labeled proteins similar to that of nontransformed cells. The K-ras oncogene activation also resulted in an overall decrease of [3H]-MVA incorporation into isopentenyl-tRNA together with an increase of unprocessed [3H]-MVA and no alteration in [3H]-MVA uptake. The effects of v-K-ras on protein prenylation could be mimicked in FRTL-5 cells by lowering the concentration of exogenous [3H]-MVA whereas increasing the [3H]-MVA concentration did not revert the alterations observed in transformed cells. Accordingly, v-K-ras expression was found to: (i) down-regulate mevalonate kinase; (ii) induce farnesyl-pyrophosphate synthase expression; and (iii) augment protein farnesyltransferase but not protein geranylgeranyl-transferase-I activity. Among these events, mevalonate kinase down-regulation appeared to be related strictly to differential protein prenylation. This study represents an example of how expression of the v-K-ras oncogene, through multiple interferences with the isoprenoid metabolic pathway, may result in the preferential farnesylation of the ras oncogene product p21(ras).

Alkyl and Aryl Transferases↗
PubMed2004

Statin blocks Rho/Rho-kinase signalling and disrupts the actin cytoskeleton: relationship to enhancement of LPS-mediated nitric oxide synthesis in vascular smooth muscle cells.

We previously demonstrated statins to enhance cytokine-mediated nitric oxide (NO) synthesis in vascular smooth muscle cells (VSMC). To clarify the mechanism by which this occurs, we evaluated the effects of fluvastatin in lipopolysaccharide (LPS)-stimulated VSMC. NO production induced by LPS was dose-dependently enhanced by fluvastatin, as were iNOS mRNA levels and iNOS protein expression. Exogenous mevalonate and geranylgeranylpyrophosphate (GGPP) dampened the stimulatory effect of fluvastatin. A pull-down assay demonstrated fluvastatin to decrease levels of GTP-bound Rho A. Moreover, a Rho-kinase inhibitor, Y-27632, was observed to enhance LPS-induced NO production. We recently demonstrated that disrupting F-actin formation dramatically potentiates the ability of LPS to induce iNOS mRNA and protein expression. In the present study, staining of F-actin with nitrobenzoxadiazole (NBD)-phallacidin demonstrated that fluvastatin significantly impairs F-actin stress fiber formation. In light of these results, the ability of statins to increase NO production is due, at least in part, to their ability to block the biosynthesis of mevalonate, thereby preventing isoprenoid biosynthesis. This inhibits Rho/Rho-kinase signalling and, in turn, disrupts the actin cytoskeleton. Further analysis of the signalling pathway by which the actin cytoskeleton affects iNOS expression might yield new insight into mechanisms of regulation of NO production.

Actins↗
PubMed1997

A partial deficiency of dehydrodolichol reduction is a cause of carbohydrate-deficient glycoprotein syndrome type I.

Carbohydrate-deficient glycoprotein (CDG) syndrome type I is a congenital disorder that involves the underglycosylation of N-glycosylated glycoproteins (Yamashita, K., Ideo, H., Ohkura, T., Fukushima, K., Yuasa, I., Ohno, K., and Takeshita, K. (1993) J. Biol. Chem. 268, 5783-5789). In an effort to further elucidate the biochemical basis of CDG syndrome type I in our patients, we investigated the defect in the multi-step pathway for biosynthesis of lipid-linked oligosaccharides (LLO) by the metabolic labeling method using [3H]glucosamine, [3H]mannose, and [3H]mevalonate. The LLO levels in synchronized cultures of fibroblasts from these patients were severalfold lower than those in control fibroblasts in the S phase, and the oligosaccharides released from LLO showed the same structural composition, Glc1 approximately 3.Man9.GlcNAc.GlcNAc, in the case of both the patients and controls. The amount of [3H]mannose incorporated into mannose 6-phosphate, mannose 1-phosphate, and GDP-mannose was greater in fibroblasts from these patients than in the control fibroblasts in the G1 period, although the ratios of these acidic mannose derivatives as indicated by the relative levels of radioactivity were the same for the two types of fibroblasts. Furthermore, upon metabolic labeling with [3H]mevalonate, the level of [3H]dehydrodolichol in fibroblasts from these patients increased in the S phase, and the levels of [3H]dolichol and [3H]dolichol-PP oligosaccharides concomitantly decreased, although the chain length distribution of the respective dolichols and dehydrodolichols was the same in the two types of fibroblasts. These results indicate that the conversion of dehydrodolichol to dolichol is partially defective in our patients and that the resulting loss of dolichol leads directly to underglycosylation.

Cells, Cultured↗
PubMedDate not supplied

Pneumocystis carinii f. sp. carinii synthesizes de novo four homologs of ubiquinone.

Ubiquinone, coenzyme Q, plays a pivotal role in electron transport and is a target for chemotherapy against a number of eukaryotic infectious agents, including Pneumocystis carinii. Coenzyme Q10 was previously identified as the major ubiquinone homolog in P. carinii isolated and purified from rat lungs; CoQ9 was also present. In contrast, CoQ9 and CoQ8 (but not CoQ10) were detected in the lungs of uninfected rat controls. These observations suggested that the pathogen synthesizes CoQ10, and perhaps CoQ9 as well. In the present study, CoQ biosynthesis in P. carinii was examined in greater detail. Radiolabeled mevalonate, a precursor of the CoQ polyprenyl chain, was incorporated in vitro into P. carinii ubiquinones. Incorporation of radiolabeled mevalonate into P. carinii CoQ was not enhanced by treating cells with lovastatin, suggesting that the cells did not transport the drug, or that a lovastatin-insensitive pathway for de novo synthesis of isoprenoids may also function in this organism. Radiolabeled precursors of the ring moiety, including shikimic acid, p-hydroxybenzoic acid, and tyrosine were also incorporated into P. carinii CoQ. Unexpectedly, it was found that not only CoQ9 and CoQ10, but also CoQ7, and CoQ8, were metabolically radiolabeled by all the precursors tested, indicating that the organism synthesizes CoQ7, CoQ8, CoQ9, and CoQ10. Metabolic radiolabeling of ubiquinones in rat lung controls was not detected in experiments using either radioactive mevalonate or p-hydroxybenzoate. Thus the incorporations measured using purified P. carinii preparations were due to the enzymes of the organism.

Animals↗
PubMed2006

Localization of the pre-squalene segment of the isoprenoid biosynthetic pathway in mammalian peroxisomes.

Previous studies have indicated that the early steps in the isoprenoid/cholesterol biosynthetic pathway occur in peroxisomes. However, the role of peroxisomes in cholesterol biosynthesis has recently been questioned in several reports concluding that three of the peroxisomal cholesterol biosynthetic enzymes, namely mevalonate kinase, phosphomevalonate kinase, and mevalonate diphosphate decarboxylase, do not localize to peroxisomes in human cells even though they contain consensus peroxisomal targeting signals. We re-investigated the subcellular localization of the cholesterol biosynthetic enzymes of the pre-squalene segment in human cells by using new stable isotopic techniques and data computations with isotopomer spectral analysis, in combination with immunofluorescence and cell permeabilization techniques. Our present findings clearly show and confirm previous studies that the pre-squalene segment of the cholesterol biosynthetic pathway is localized to peroxisomes. In addition, our data are consistent with the hypothesis that acetyl-CoA derived from peroxisomal beta-oxidation of very long-chain fatty acids and medium-chain dicarboxylic acids is preferentially channeled to cholesterol synthesis inside the peroxisomes without mixing with the cytosolic acetyl-CoA pool.

Acetyl-CoA C-Acetyltransferase↗
PubMed1992

Isoprenoid requirement for intracellular transport and processing of murine leukemia virus envelope protein.

Lovastatin blocks the biosynthesis of the isoprenoid precursor, mevalonate. When Friend murine erythroleukemia (MEL) cells are cultured in medium containing lovastatin, the precursor of murine leukemia virus envelope glycoprotein (gPr90env) fails to undergo proteolytic processing, which normally occurs in the Golgi complex. Consequently, newly synthesized envelope proteins are not incorporated into viral particles that are shed into the culture medium. gPr90env appears to be localized in a pre-Golgi membrane compartment, based on its enrichment in subcellular fractions containing NADPH-cytochrome c reductase activity and the sensitivity of its carbohydrate chains to digestion with endoglycosidase H. Arrest of gPr90env processing occurs at concentrations of lovastatin that are not cytostatic, and the effect of the inhibitor is prevented by addition of mevalonate to the medium. The low molecular mass GTP-binding proteins, rab1p and rab6p, which are believed to function in early steps of the exocytic pathway, are normally modified posttranslationally by geranylgeranyl isoprenoids. However, in MEL cells treated with 1 microM lovastatin, nonisoprenylated forms of these proteins accumulate in the cytosol prior to arrest of gPr90env processing. These observations suggest that lovastatin may prevent viral envelope precursors from reaching the Golgi compartment by blocking the isoprenylation of rab proteins required for ER to Golgi transport.

Animals↗
PubMedDate not supplied

Endothelium modulates contractile response to simvastatin in rat aorta.

Simvastatin is an inhibitor of HMG-CoA reductase used in the treatment of hypercholesterolemia. In the present study simvastatin-induced contraction was observed in rat aortic thoracic rings, this effect increased when the endothelium was removed and when NO synthase was blocked by L-NOARG (3 x 10(-5) M). The contractile effect of simvastatin on intact aortic rings diminished when cyclo-oxygenase was inhibited with indomethacin (10(-5) M). Also in the presence of endothelium, pretreatment with mevalonate (1 mM), the product of HMG-CoA reductase activity, significantly inhibited the contraction. In other experiments carried out on endothelium-removed preparations and in medium containing the calcium antagonist, diltiazem (10(-5) and 10(-6) M), the contraction dose-response curves were significantly reduced and the same happened in the presence of the inhibitor of sarcoplasmic reticulum Ca-2+-ATPase, cyclopiazonic acid (CPA) (3 x 10(-6) M). The results suggest that simvastatin might increase intracellular calcium concentration. This effect could lead to an activation of NO synthase and cyclooxygenase pathways in endothelial cells and to contraction in vascular smooth muscle cells. This rise in Ca2+ concentration could be due to an inhibition of isoprenoid synthesis prevented by mevalonate.

Animals↗
PubMed1988

Cyclic AMP decreases LDL catabolism and cholesterol synthesis in the human hepatoma cell line HepG2.

A 24h pretreatment of the human hepatoma cell line HepG2 with dibutyryl cyclic AMP in the presence of theophylline induced a dose dependent decrease in low density lipoprotein binding, uptake and degradation. This effect is most likely due to a reduction of the LDL receptor number. Sterol synthesis from sodium acetate is markedly inhibited, either in the presence or absence of LDL, whereas synthesis from mevalonic acid is unchanged. Cyclic AMP also induced a decrease in hydroxy methyl glutaryl coenzyme A reductase activity. These effects of cyclic AMP might be involved in some hormonal regulation of the LDL pathway and cholesterol metabolism in the liver.

Acetates↗
PubMed2002

Statin-induced apoptosis of vascular endothelial cells is blocked by dexamethasone.

Statins block de novo synthesis of cholesterol by inhibiting the enzyme, HMG CoA reductase. The product of this reaction, mevalonic acid, is also a precursor of isoprenoids, molecules required for the activation of signalling G-proteins, such as Ras. Signal transduction pathways involving Ras are important for cell survival and this may be why statins induce apoptotic death of several cell types. Given that statins are used to treat vascular disease, it is surprising that no studies have been conducted on vascular endothelial cells. For this reason, we have tested the effect of fluvastatin (FS) on the endothelial cell line EA.hy 926. Here we show that FS, at concentrations from 1 to 2 microM, blocks growth and induces apoptosis of the endothelial cell line, EA.hy 926. As considerable redundancy exists in cell signalling pathways for cell survival, toxicity of FS under more physiological conditions might be prevented by pathways that do not require Ras, such as those activated by adrenal or sex steroids. To test this hypothesis, first RT-PCR analysis was performed for nuclear receptor mRNA expression. This revealed the presence of mRNA for the androgen receptor (AR) and glucocorticoid receptor (GR). The effect of the AR agonist, dihydrotestosterone (DHT), and the GR agonist, dexamethasone (Dex), was then tested. Whilst DHT (100 nM) had no effect on FS-induced cell death, Dex (1 microM) blocked FS-induced apoptosis. Cell cycle analysis revealed that 24 h exposure to FS prevented cells from leaving G(1) and 24-48 h later a marked sub-G(1) peak was observed. Dex was able to reduce the sub-G(1) peak, but it failed to reduce accumulation of cells in G(1). Further studies revealed that, in addition to blocking FS-induced apoptosis, Dex was able to block apoptosis of EA.hy 926 cells induced by serum deprivation, tumour necrosis factor-alpha, oxidants, DNA damage and mitochondrial disruption. This study strongly suggests that glucocorticoids have a role to play in preventing vascular injury and they may provide a reason why statins are apparently not toxic to vascular endothelial cells in vivo.

Androgen Receptor Antagonists↗
PubMed1986

Sterol composition and biosynthesis in mouse salivary glands.

Sterol components of mouse submandibular, sublingual and parotid glands were studied by thin-layer and gas-liquid chromatography. The major sterol was cholesterol (5-cholesten-3 beta-ol; 26.7, 28.0, 18.8 micrograms/mg protein respectively), with minor amounts of squalene, lathosterol (5 alpha-cholest-7-en-3 beta-ol), desmosterol (cholesta-5,24-dien-3 beta-ol), lanosterol (4,4',14-trimethyl-5 alpha-cholesta-8,24-dien-3 beta-ol), dihydrolanosterol (4,4',14-trimethyl-5 alpha-cholest-8-en-3 beta-ol) and methylstenol. Chromatograms of salivary sterols were similar to those of liver, and different from those of skin in which the amount of lathosterol was much higher. Administration of the anticholesterolaemic agent, 20,25-diazacholesterol, resulted in accumulation of desmosterol in all tissues tested, and additional sterols also accumulated in skin. The gas-liquid chromatographic profiles of salivary sterols from the treated animals were similar to those of liver, but different from those of skin. Thus sterols were synthesized in salivary glands and the biosynthetic pathway was via C24-unsaturated side-chain intermediates, as in liver. This was verified by showing that [2-14C]-mevalonate was incorporated into sterols in vitro when it was incubated with homogenates of these glands.

Animals↗