Effects of simvastatin on pro-inflammatory cytokines in patients with hypercholesterolemia.

[Article in English, Polish]

Muryn Z.

Department of Internal Diseases, Silesian Medical Academy, Bytom, Poland.

BACKGROUND: The role of inflammation in the development of atherosclerosis and its complications has been recently documented. Pro-inflammatory cytokines are among many postulated factors. It is possible that the imbalance between protective cytokines and cytokines affecting endothelial function is one of the underlying mechanisms of myocardial ischaemia. AIM: To examine the effects of simvastatin on IL-2 and TNFalpha levels in patients with hypercholesterolemia. METHODS: The study group consisted of 64 males (age 20-65 years) with hypercholesterolemia. The control group was composed of 10 healthy male volunteers (age 25-40 years) with normal lipid profile. Total cholesterol, LDL-cholesterol, IL-2 and TNFalpha were measured in both groups at baseline, after three months of dietary treatment, and after a further three months of simvastatin therapy. RESULTS: Simvastatin caused a significant decrease in the total and LDL-cholesterol levels compared both with baseline measurements (p=0.0001) and after dietary treatment (p=0.0001). Moreover, simvastatin significantly reduced the IL-2 plasma concentration (p=0.0003). There were no significant differences between IL-2 levels before and following dietary treatment. The TNFalpha serum concentration significantly decreased following the implementation of diet (p=0.0001). Subsequent simvastatin therapy caused further decrease in the TNFalpha serum concentration but this difference did not achieve statistical significance. CONCLUSIONS: A hypolipemic diet significantly decreases TNFalpha serum concentration without affecting the IL-2 level. The subsequent simvastatin therapy significantly reduces IL-2 but not TNFalpha when compared with the post-diet values.

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Simvastatin suppresses LPS-induced Akt phosphorylation in the human monocyte cell line THP-1.

Corbett SA.

Department of Surgery, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903, USA.

BACKGROUND: Activation of the small GTPase, Rac, requires post-translational modification by isoprenylation. Statins interfere with this process by blocking the synthesis of isoprenoid intermediates. The protein kinase Akt is a multifunctional regulator of cell behavior that has been linked to Rac activation. We have shown that lipopolysaccharide (LPS) stimulation leads to Rac activation in THP-1 cells. Therefore, we hypothesized that LPS stimulation would also activate Akt, a downstream effector of Rac, and that this may be blocked by statin pretreatment. MATERIALS AND METHODS: THP-1 cells were maintained in 1% fetal calf serum with or without 20 microM simvastatin for 24 h, followed by LPS stimulation for increasing time. Cytoskeletal changes were observed using Alexa-Phalloidin. Akt was immunoprecipitated from total cell lysate. Activated Akt was detected by immunoblotting with a phospho-Akt antibody and was quantified by image densitometry. RESULTS: LPS stimulation of THP-1 cells results in membrane ruffling and cell polarization. Furthermore, LPS increased Akt activation in THP-1 cells when compared with the nonstimulated controls. Akt phosphorylation peaked after 15 min of LPS stimulation and was suppressed by pretreatment with simvastatin. CONCLUSIONS: These data demonstrate that LPS stimulation leads to increased Akt phosphorylation, which can be suppressed with simvastatin pretreatment. This suggests one possible mechanism through which simvastatin could modulate LPS-induced signaling events in monocytes to improve the host response to Gram-negative infections.

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Effects of simvastatin on plasma lipoproteins and response to arterial injury in wild-type and apolipoprotein-E-deficient mice.

Reis ED.

Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA. robin.choudhury cardiov.ox.ac.uk

OBJECTIVE: To test the non-lipid-lowering effects of simvastatin on the response to injury in normolipidemic and hyperlipidemic mice. METHODS AND RESULTS: Wild-type (WT) mice (n = 40) and hyperlipidemic apolipoprotein-E-deficient (apoE(-/-)) mice (n = 40) received normal chow or chow containing simvastatin 100 mg/kg/day prior to bilateral femoral artery wire injury. Intimal hyperplasia and plasma cholesterol concentration were quantified after 4 weeks. Plasma cholesterol in WT mice treated or untreated with simvastatin was similar (100.9 +/- 6.6 vs. 94.3 +/- 17.5 mg/dl). Simvastatin did not affect intimal hyperplasia. In apoE(-/-) mice, intimal hyperplasia was increased 2.3-fold relative to WT mice (17090 +/- 4998 vs. 39490 +/- 16190; p < 0.001). In apoE(-/- )mice, simvastatin caused a paradoxical increase in plasma cholesterol (1094 +/- 60.3 vs. 658 +/- 66.8 mg/dl; p < 0.001), confirmed by FPLC. This was associated with a further increase in intimal area (39490 +/- 16190 vs. 55420 +/- 22590 mm(2); p < 0.01). CONCLUSIONS: (1). Simvastatin had no effect on plasma cholesterol or the response to arterial injury in normolipidemic WT mice; (2). hyperlipidemia was associated with markedly increased intimal hyperplasia, and (3). simvastatin treatment of apoE(-/-) mice caused paradoxical hyperlipidemia and increased intimal hyperplasia. Copyright 2004 S. Karger AG, Basel

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Evaluation of simvastatin antioxidant effects.

Artenie R.

Biochemistry Department, Gr.T. Popa University of Medicine and Pharmacy, Iasi.

3-Hydroxy-3-methyl-coenzyme A reductase (HMG-CoA reductase) which transforms 3-hydroxy-3-methylglutaril-coenzyme A (HMG-CoA) in mevalonate, is the rate limiting enzyme in cholesterol biosynthesis. In our study, from HMG-CoA reductase's known inhibitors, we used simvastatin (ZOCOR), which is a semi synthetic derivative of the second generation. The study was performed on 25 subjects (12 men and 12 women) aged 33-67 yo, with hypercholesterolemia, which have received simvastatin, 10 mg daily for 8 months. Under treatment with simvastatin we obtained a significant decrease of total cholesterol (p < 0.0001) and an improvement of enzymatic antioxidant parameters: superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT). In conclusion, simvastatin therapy determines a significant decrease in SOD, GPx, CAT, and an increase in CAT/SOD and GPx/SOD ratios.

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Simvastatin decreases nitric oxide overproduction and reverts the impaired vascular responsiveness induced by endotoxic shock in rats.

Antunes-Rodrigues J.

Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, SP, Brazil.

Lipopolysaccharides (LPS) can be used to induce experimental endotoxic shock, which is characterized by a significant decrease in mean arterial pressure (MAP) and a decreased vasoconstrictor response that have been attributed to excessive nitric oxide production. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), in addition to lowering serum cholesterol levels, exert many pleiotropic effects, including anti-inflammatory action. In the present study, we investigated the effect of simvastatin, an HMG-CoA reductase inhibitor, on the production of nitric oxide and the cardiovascular response to LPS. Male Wistar rats were pretreated with different doses of simvastatin (10, 20, 40, and 80 mg/kg, i.p.) or saline 20 min before i.v. injection of LPS (1.5 mg/kg) or saline (control). MAP was continuously recorded and nitrate plasma concentration was determined during the 6-h experimental session at 1-h intervals. The pressor response to phenylephrine (1 microg/kg) was evaluated before and 6 h after LPS administration. In the LPS-treated group, there was a time-dependent increase in nitrate plasma concentration (P<0.001), and this response was decreased in simvastatin pretreated rats (P<0.001). We also observed that LPS decreased the pressor response to phenylephrine (P<0.001), an effect that was reverted by simvastatin pretreatment (P<0.05). However, simvastatin did not modify the decrease of MAP induced by LPS. We concluded that simvastatin decreases nitrate plasma concentration in response to LPS and recovers vascular responsiveness during an experimental endotoxic shock. These data suggest the potential use of HMG-CoA reductase inhibitors as a coadjuvant in the treatment of septic shock.

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Effect of simvastatin in familial hypercholesterolemia on the affinity of electronegative low-density lipoprotein subfractions to the low-density lipoprotein receptor.

Sanchez-Quesada JL.

Department of Biochemistry, Hospital de la Santa Creu i Sant Pau, and Department of Biochemisty and Molecular Biology, University Autonoma de Barcelona, Spain.

The effect of simvastatin therapy on the biologic characteristics of the electronegative low-density lipoprotein (LDL) subfraction of patients with familial hypercholesterolemia (FH) was studied. Total LDL, isolated from FH plasma at 0, 3 and 6 months of simvastatin treatment, was subfractionated into electropositive LDL (LDL[+]) and electronegative LDL (LDL[-]) by anion exchange chromatography. LDL isolated from healthy normolipemic (NL) subjects was used as a control. The LDL(-) proportion was twofold higher in patients with FH than in NL subjects (17.6 +/- 1.6% vs 7.8 +/- 1.5%, respectively; p <0.05) and was progressively reduced by simvastatin therapy (15.7 +/- 1.6% at 3 months; 13.8 +/- 2.5% at 6 months; p <0.05). Both LDL subfractions from patients with FH had a higher relative cholesterol content and decreased apolipoprotein B and triglycerides than NL subfractions. Simvastatin progressively induced changes in lipid content of both LDL subfractions in patients with FH, and lipid composition was closer to these subfractions in NL subjects after 6 months of therapy. Binding displacement experiments in human fibroblasts demonstrated that LDL(-) from both groups of subjects had a lower affinity of binding to the LDL receptor that LDL(+). In addition, LDL(+) in patients with FH presented an intermediate binding affinity between LDL(-) and LDL(+) in NL subjects. Simvastatin-induced changes in LDL composition were accompanied by a progressive increase in affinity of LDL(+) and LDL(-) in patients with FH. After 6 months of therapy, LDL(+) in FH had an affinity similar to that of LDL(+) in NL subjects. The LDL(-)-induced release of chemokines interleukin-8 and monocyte chemotactic protein-1 from cultured endothelial cells was twofold higher compared with that of LDL(+). No difference in chemokine release between patients with FH and NL subjects or the effect of simvastatin were observed. We conclude that simvastatin therapy was able to modify LDL subfraction composition in subjects with FH and increase their affinity to the LDL receptor. This improvement could contribute to the observed reduction in LDL(-) proportion induced by simvastatin.

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