[Studies on the simvastatin effect on the artery of atherosclerotic rabbit using proteomics approaches]

[Article in Chinese]

Yang PY.

Chemistry Department, Fudan University, College of Pharmacy, Second Military Medical University, Shanghai 200433, China.

AIM: To evaluate the inhibitory effect of simvastatin via investigating the overall expression level of proteins in the artery of atherosclerotic rabbit. METHODS: Experimental model was established by feeding the rabbits a high fat diet (cholesterol 0.5 g.kg-1.d-1, lard 0.5 mL.kg-1.d-1) for 8 weeks. Then simvastatin (5 mg.kg-1) were fed for 4 weeks to the rabbits. The overall protein levels were measured using two-dimensional gel electrophoresis and a PDQUEST data processing. RESULTS: Twenty nine protein spots showed significant quantitative changes in comparison with the normal and the diseased rabbits. Furthermore, after the diseased rabbit having taken simvastatin, an obvious decay of symptom of fatty liver was observed, and the intensity of most spots has not been back-regulated. CONCLUSION: Simvastatin facilitates the metabolism of fat in the blood, but the lesion of the internal wall of the atherosclerotic artery cannot be restored.

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Apoptosis induced by simvastatin in rat vascular smooth muscle cell through Ca2+-calpain and caspase-3 dependent pathway.

Zhu L.

Department of Cardiology, The Second Affiliated Hospital, Zhejiang University College of Medicine, Jiefang Road 88#, Hangzhou, Zhejiang 310009, China. chenggang_9 hotmail.com

Several studies have shown that simvastatin induces apoptosis in a variety of cell lines including vascular smooth muscle cells (VSMCs), but the exactly mechanisms involved in it is not very clear. The aim of this study was to investigate the mechanisms and signal pathways involved in apoptosis induced by simvastatin. When exposed to 30 microM simvastatin, [Ca2+]i in VSMCs increased with time and reached to 336 +/- 52 nM at 6 h, more than four-fold of control (P<0.01, n=5). Verapamil (80 microM), a membrane voltage-dependent Ca2+ channel blocker, attenuated simvastatin-induced augmentation of free calcium concentration from 336 +/- 52 nM to 144 +/- 34 nM (P<0.01). After being exposed to 30 microM simvastatin for 8 h, calpain activity markedly increased (P<0.05, n=4) and reached to more than three-fold of control at 12 h (P<0.01). Caspase-3 was also activated by simvastatin after 12 h. Verapamil and PD150606, a cell-permeable selective calpain inhibitor, significantly inhibited simvastatin-induced augmentation of calpain activity and blocked caspase-3 activation, respectively. Furthermore, 80 microM verapamil and 100 microM PD150606 decreased simvastatin-induced apoptosis rate from 24.2 +/- 1.7% to 7.9 +/- 0.6% (P<0.01, n=4) and 9.5 +/- 1.9% (P<0.01), respectively and also prevented simvastatin-induced DNA laddering. In conclusion, we indicated that simvastatin increases cytosolic free calcium concentration mainly through calcium influx from extracellular solution and then induces apoptosis by activating caspase-3 via calcium-dependent protease calpain.

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Pharmacological modulation of fatty acid desaturation and of cholesterol biosynthesis in THP-1 cells.

Galli C.

Department of Pharmacological Sciences, University of Milan, 20133 Milano, Italy. patrizia.rise unimi.it

In THP-1 cells, simvastatin decreases, in a concentration-dependent manner, cholesterol synthesis and increases linoleic acid (LA) conversion to its long-chain derivatives, in particular to arachidonic acid, activating delta6 and delta5 fatty acid (FA) desaturases. The intermediates in cholesterol synthesis, mevalonate and geranylgeraniol, partially reverse the effects of simvastatin on the LA conversion. The aims of this work were to evaluate: (i) the correlation between cholesterol synthesis and desaturase activity and (ii) the possible involvement of protein isoprenylation in desaturase activity, assessed through pharmacological treatments. THP-1 cells were incubated with [1-14C]LA or with [1-14C]di-homo-gamma-linolenic acid (DHGLA) and treated with simvastatin or with curcumin and nicardipine, inhibitors of desaturases. Curcumin was more active than nicardipine in inhibiting LA and DHGLA conversion: 20 microM curcumin, alone or with simvastatin, totally inhibited delta6 and delta5 desaturation steps; 10 microM nicardipine only partially inhibited the enzymes, being more active on delta5 desaturase. Simvastatin treatment decreased the incorporation of acetate in cholesterol (-93.8%) and cholesterol esters (-70.2%), as expected. Curcumin and nicardipine also decreased cholesterol synthesis and potentiated simvastatin. Finally, the isoprenylation inhibitors (perillic acid and GGTI-286) neither affected the conversion of LA nor inhibited the delta5 desaturase activity. In conclusion, our results indicate that there is no direct relationship between cholesterol synthesis and desaturase activity. In fact, simvastatin decreased cholesterol synthesis and enhanced LA conversion (mainly delta5 desaturation), whereas curcumin and nicardipin decreased delta5 desaturation, with a limited effect on cholesterol synthesis.

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Effect of simvastatin on the uptake and metabolic conversion of palmitic, dihomo-gamma-linoleic and alpha-linolenic acids in A549 cells.

de Bravo MG.

Instituto de Investigaciones Bioqui;micas de La Plata (INIBIOLP), CONICET-UNLP, Facultad de Ciencias Medicas, Calle 60 y 120, La Plata 1900, Argentina.

It is well known that simvastatin affects cholesterol synthesis. Furthermore it inhibits growth and proliferation and perturbs fatty acid metabolism in some cell lines. We have studied the effects of simvastatin on the uptake and metabolism of exogenous fatty acid in the human lung adenocarcinoma A549 cells. Simvastatin inhibited the proliferation of A549, and caused an increment in phospholipid/cholesterol ratio due to an increment in phospholipid content without affecting cholesterol content. All the fatty acids were uptaken and metabolized in both control and treated cells. The conversion of palmitic, linoleic and dihomo-gamma-linoleic acids to their metabolites and products/precursor ratios for the desaturation and elongation reactions showed that simvastatin enhanced the Delta5 desaturation step and altered some elongating steps. The machinery for unsaturated fatty acid synthesis in A549 is quite sensitive to simvastatin and its effects could have important implication taking into account that highly unsaturated fatty acids are involved in the regulation of diverse cellular functions by themselves or through their metabolites.

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[Simvastatin induces osteoblastic differentiation of bone marrow stromal cells]

[Article in Chinese]

Ma Q.

Department of Orthopedics, Peking University Third Hospital, Beijing 100083, China.

OBJECTIVE: To observe the effect of simvastatin on osteoblastic cell differentiation of bone marrow stromal cells in vitro, and to elucidate the mechanisms of anabolic effect of simvastatin on bone formation. METHODS: Bone marrow stromal cells from femur and tibia of adult female BALB-C mice were cultured in vitro, after being treated with different concentrations of simvastatin for 72 h, changes of mRNA level of osteocalcin (OCN) were detected by RT-PCR, change of OCN, and osteopontin (OPN) expression were examined by Western blot, and the changes of cellular alkaline phosphatase activity (ALP) were examined by histochemistry and enzymologic measurement. RESULTS: After bone marrow stromal cells were treated with different concentration of simvastatin for 72 h, level of OCN mRNA increased, and expression of OCN and OPN also increased in a concentration-dependent manner, and cellular ALP activity significantly increased in a concentration-dependent manner. CONCLUSION: Simvastatin can stimulate osteoblastic differentiation, and improve cellular ALPase activity with high expression of osteocalcin and osteopontin in vitro. These may be parts of the mechanism of anabolic effect of simvastatin on bone formation.

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Effects of simvastatin administration in an experimental model of cancer cachexia.

Baccino FM.

Department of Clinical Medicine, University La Sapienza, Rome, Italy. maurizio.muscaritoli uniroma1.it

OBJECTIVE: We evaluated whether statins, in view of their anti-inflammatory properties, may effectively prevent the onset or modulate the severity of muscle wasting during cancer cachexia. METHODS: Simvastatin was administered to rats bearing the Yoshida AH-130 ascites hepatoma, a well-studied cytokine-dependent experimental model of cancer cachexia. RESULTS: Quite surprisingly, the drug negatively affected the wasting pattern induced by the AH-130 hepatoma. In fact, the administration of simvastatin to tumor hosts induced a further weight reduction of all the tissues examined except for the soleus, in the absence of significant effects of simvastatin on tumor growth or on food intake. No effects were observed after simvastatin administration in control animals, with the exception of a significant (P < 0.05) reduction in heart weight. CONCLUSIONS: Simvastatin administration, although capable of negatively modulating the inflammatory response, did not prevent muscle wasting in this experimental model of cancer cachexia. Moreover, the further muscle loss observed in simvastatin-treated tumor-bearing animals suggests that a note of caution should be introduced in treating cancer patients with statins in view of the possible occurrence of harmful side effects.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14624942&dopt=Abstract simvastatin, Zocor