Comparison of the effects of atorvastatin versus simvastatin on subclinical atherosclerosis in primary preventionas determined by electronbeam tomography.

Harman SM.

Beth Israel Medical Center, New York, New York, USA. hhecht aol.com

This study was designed to evaluate the effects of lipid-lowering therapy by atorvastatin versus simvastatin on calcified plaque progression, as determined by serial electron beam tomography (EBT), in primary prevention patients. In this observational study, serial EBT was performed before and after 1.2 years of atorvastatin (n = 103) and simavastatin therapy (n = 46); approximately 50% of each group was on niacin as well, in similar doses. There were no differences in demographic parameters between the groups. Total, low-density lipoprotein (LDL), and non-high-density lipoprotein (HDL) cholesterol were significantly higher in the atorvastatin group before treatment. Before treatment, EBT calcium score and volume scores were 469 and 378, respectively, in the atorvastatin patients, and 388 and 307, respectively, in the simvastatin patients (p = NS, atorvastatin vs simvastatin). After treatment, there were no differences in any lipid or EBT values between the groups. Post-treatment total cholesterol and LDL cholesterol were 156 and 79 mg/dl, respectively, in the atorvastatin cohort and 154 and 76 mg/dl, respectively, in the simvastatin group (p = NS). Calcium score and volume progressed 10.8%/year and 8.5%/year, respectively, in the atorvastatin group, and 7.5%/year and 7.8%/year in the simvastatin group (p = NS, atorvastatin vs simvastatin). We conclude that aggressive treatment with atorvastatin and simvastatin in the primary prevention population, to similar lipid levels, is associated with equal progression of EBT-determined calcified plaque. This suggests that these hydroxymethylglutaryl coenzyme A reductase inhibitors exhibit a "class effect" with respect to progression of subclinical atherosclerosis.

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[Effect of simvastatin on bone morphogenetic protein-2 expression and alkaline phosphatase activity of bone marrow stromal cell]

[Article in Chinese]

Guo ZQ.

Department of Orthopedic Surgery, Third Hospital of Peking University, Beijing, P. R. China 100038. songchunli 263.net

OBJECTIVE: To study the effect of simvastatin on the expression of bone morphogenetic protein-2 (BMP-2) and alkaline phosphates (ALP) activity in the primary cultured bone marrow stromal cells, and to elucidate the mechanism of the anabolic osteogenetic effect of simvastatin. METHODS: Bone marrow stromal cells in femur and tibia of adult mouse were cultured in vitro. after treated with different concentrations of simvastatin (0, 0.1, 0.2, 0.5 and 1.0 mumol/L) or recombinant human BMP-2 for 72 hours, ALP activity of bone marrow stromal cells was determined. BMP-2 expression of bone marrow stromal cells was analyzed by using immunocytochemistry and Western blotting. RESULTS: After treated with simvastatin for 72 hours, BMP-2 expression increased, while little BMP-2 expression could be observed in the control group. ALP activity also increased in a dose-dependent manner; t-test showed that ALP activity in the group which concentrations of simvastatin were 0.5 mumol/L (t = 2.35, P = 0.041), 1.0 mumol/L (t = 2.348, P = 0.041) had significant difference when compared with control group. CONCLUSION: Simvastatin lead to high expression of BMP-2 in bone marrow stromal cells, via the increased auto- or para-crine of BMP-2, and ALP activity increased. These may be parts of the mechanism on the anabolic osteogenetic effect of simvastatin.

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Discordant expression of the sterol pathway in lens underlies simvastatin-induced cataracts in Chbb: Thom rats.

Sexton PS.

Department of Biochemistry, Kirksville College of Osteopathic Medicine, Kirksville, MO, USA. rcenedella kcom.edu

Simvastatin rapidly induced cataracts in young Chbb:Thom (CT) but not Sprague Dawley (SD) or Hilltop Wistar (HW) rats. Oral treatment for 14 but not 7 days committed CT rat lenses to cataract formation. The cholesterol to phospholipid molar ratio in lenses of treated CT rats was unchanged. Differences between strains in serum and ocular humor levels of simvastatin acid poorly correlated with susceptibility to cataracts. No significant differences were found between rat strains in the capacity of simvastatin acid to inhibit lens-basal sterol synthesis. Prolonged treatment with simvastatin comparably elevated HMG-CoA reductase protein and enzyme activity in lenses of both cataract resistant and sensitive strains. However, in contrast to SD and HW rats, where sterol synthesis was markedly increased, sterol synthesis in CT rat lenses remained at baseline. Discordant expression of sterol synthesis in CT rats may be due to inadequate upregulation of lens HMG-CoA synthase. HMG-CoA synthase protein levels, and to a much lesser extent mRNA levels, increased in lens cortex of SD but not CT rats. Because upregulation of the sterol pathway may result in increased formation of isoprene-derived anti-inflammatory substances, failure to upregulate the pathway in CT rat lenses may reflect an attenuated compensatory response to injury that resulted in cataracts.

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Simvastatin stimulates VEGF release via p44/p42 MAP kinase in vascular smooth muscle cells.

Kozawa O.

Department of Pharmacology, Gifu University School of Medicine, Gifu 500-8705, Japan.

It has been shown that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) modulate vascular smooth muscle cell functions. In the present study, we investigated the effect of simvastatin on vascular endothelial growth factor (VEGF) release, and the underlying mechanism, in a rat aortic smooth muscle cell line, A10 cells. Administration of simvastatin increased the VEGF level in rat plasma in vivo. In cultured cells, simvastatin significantly stimulated VEGF release in a dose-dependent manner. Simvastatin induced the phosphorylation of p44/p42 MAP kinase but not p38 MAP kinase or SAPK (stress-activated protein kinase)/JNK (c-Jun N-terminal kinase). PD98059 and U-0126, inhibitors of the upstream kinase that activates p44/p42 MAP kinase, significantly reduced the simvastatin-induced VEGF release in a dose-dependent manner. The phosphorylation of p44/p42 MAP kinase induced by simvastatin was reduced by PD98059 or U-0126. Moreover, a bolus injection of PD98059 truly suppressed the simvastatin-increased VEGF level in rat plasma in vivo. These results strongly suggest that p44/p42 MAP kinase plays a role at least partly in the simvastatin-stimulated VEGF release in vascular smooth muscle cells.

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Statins augment vascular endothelial growth factor expression in osteoblastic cells via inhibition of protein prenylation.

Horiuchi N.

Department of Biochemistry, Ohu University School of Dentistry, Koriyama 963-8611, Japan.

Statins such as simvastatin are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that inhibit cholesterol synthesis. We presently investigated statin effects on vascular endothelial growth factor (VEGF) expression in osteoblastic cells. Hydrophobic statins including simvastatin, atorvastatin, and cerivastatin-but not a hydrophilic statin, pravastatin-markedly increased VEGF mRNA abundance in nontransformed osteoblastic cells (MC3T3-E1). Simvastatin (10(-6) M) time-dependently augmented VEGF mRNA expression in MC3T3-E1 cells, mouse stromal cells (ST2), and rat osteosarcoma cells (UMR-106). According to heterogeneous nuclear RNA and Northern analyses, 10(-6) M simvastatin stimulated gene expression for VEGF in MC3T3-E1 cells without altering mRNA stability. Transcriptional activation of a VEGF promoter-luciferase construct (-1128 to +827), significantly increased by simvastatin administration. As demonstrated by gel mobility shift assay, simvastatin markedly enhanced the binding of hypoxia-responsive element-protein complexes. These results indicate that the stimulation of the VEGF gene by simvastatin in MC3T3-E1 cells is transcriptional in nature. VEGF secretion into medium was increased in MC3T3-E1 by 10(-6) M simvastatin. Pretreating MC3T3-E1 cells with mevalonate or geranylgeranyl pyrophosphate, a mevalonate metabolite, abolished simvastatin-induced VEGF mRNA expression; manumycin A, a protein prenylation inhibitor, mimicked statin effects on VEGF expression. The effect of simvastatin was blocked by pretreatment with wortmannin and LY294002, specific phosphatidylinositide-3 kinase inhibitors. Simvastatin enhanced mineralized nodule formation in culture, whereas coincubation with mevalonate, geranylgeranyl pyrophosphate, LY294002, or VEGF receptor 2 inhibitor (SU1498) abrogated statin-induced mineralization. Thus, statins stimulate VEGF expression in osteoblasts via reduced protein prenylation and the phosphatidylinositide-3 kinase pathway, promoting osteoblastic differentiation.

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A novel anti-inflammatory role for simvastatin in inflammatory arthritis.

McInnes IB.

Department of Immunology, Glasgow Royal Infirmary, University of Glasgow, Glasgow, United Kingdom.

3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) exert favorable effects on lipoprotein metabolism, but may also possess anti-inflammatory properties. Therefore, we explored the activities of simvastatin, a lipophilic statin, in a Th1-driven model of murine inflammatory arthritis. We report in this study that simvastatin markedly inhibited not only developing but also clinically evident collagen-induced arthritis in doses that were unable to significantly alter cholesterol concentrations in vivo. Ex vivo analysis demonstrated significant suppression of collagen-specific Th1 humoral and cellular immune responses. Moreover, simvastatin reduced anti-CD3/anti-CD28 proliferation and IFN-gamma release from mononuclear cells derived from peripheral blood and synovial fluid. Proinflammatory cytokine production in vitro by T cell contact-activated macrophages was suppressed by simvastatin, suggesting that such observations have direct clinical relevance. These data clearly illustrate the therapeutic potential of statin-sensitive pathways in inflammatory arthritis.

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