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PubMed1992

Effect of simvastatin on qualitative and quantitative changes of lipoprotein metabolism in CAPD patients.

The efficacy of simvastatin, a competitive inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A reductase, was investigated in 12 patients treated with continuous ambulatory peritoneal dialysis (CAPD), displaying hypercholesterolemia and moderate hypertriglyceridemia. After a 4-week placebo period, simvastatin was administered in increasing doses over a period of 3 months (1st month 10 mg; 2nd month 20 mg and 3rd month 40 mg day-1). Simvastatin reduced total serum cholesterol (300.0 +/- 15.5 vs. 193.0 +/- 8.0; -35%), LDL cholesterol (203.8 +/- 13.0 vs. 104.7 +/- 6.0; -48.0%) as well as apolipoprotein B (132.3 +/- 6.6 vs. 77.8 +/- 2.7 mg/dl; -40%). Furthermore, the ratio of LDL apo B/LDL cholesterol increased significantly (0.55 +/- 0.016 vs. 0.64 +/- 0.027). Another remarkable effect was the reduction of cholesterol concentration in VLDL (47.8 +/- 5.6 vs. 30.4 +/- 5.2; -35%). Therefore, the ratio of triglycerides/cholesterol in VLDL increased (3.57 +/- 0.3 vs. 4.28 +/- 0.29), indicating VLDL formation poor in cholesterol and rich in triglycerides. However, HDL cholesterol increased significantly from 48.6 +/- 4.4 to 57.9 +/- 5.3 mg/dl (23%). Lipoprotein(a) levels were increased as compared to controls (420 +/- 73 vs. 145 +/- 26 U/l), but were not influenced significantly by simvastatin treatment (539 +/- 99 U/l, 3rd month). No evidence for notable clinical side effects and laboratory abnormalities were reported. Measurement of simvastatin plasma levels 12 h after drug administration (single dose 40 mg) showed no detectable plasma values. At present, it appears that CAPD patients with high serum cholesterol are good candidates for the treatment with HMG-CoA reductase inhibitors.

Adult↗
PubMed2002

Simvastatin reduces expression of cytokines interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 in circulating monocytes from hypercholesterolemic patients.

OBJECTIVE: A number of studies have shown that statins decrease morbidity and mortality in patients with cardiovascular diseases. The anti-inflammatory effects of statins have recently been implicated in the clinical benefit that can be obtained in the treatment of atherosclerosis. Little is known about the mechanisms by which statins counteract inflammation. METHODS AND RESULTS: In this study, we asked whether simvastatin can influence in vitro and in vivo production of the proinflammatory cytokines interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1. A total of 107 hypercholesterolemic patients were treated with simvastatin. As measured by ELISA, serum levels of cytokines significantly decreased after 6 weeks of treatment (P<0.05). Furthermore, simvastatin decreased the expression of IL-6, IL-8, and monocyte chemoattractant protein-1 mRNA in peripheral blood mononuclear cells. Similar results were obtained in vitro by using cultured human umbilical vein endothelial cells and peripheral blood mononuclear cells from healthy normolipemic donors. Exposure to simvastatin, atorvastatin, or cerivastatin caused downregulation of the expression of cytokine mRNA in a time- and dose-dependent manner. Furthermore, all statins tested were able to reduce the concentrations of cytokines in cellular and extracellular fractions of human umbilical vein endothelial cells (P<0.05). CONCLUSIONS: Our data show that simvastatin is anti-inflammatory through the downregulation of cytokines in the endothelium and leukocytes. These effects may explain some of the clinical benefits of these drugs in the treatment of atherosclerosis.

Aged↗
PubMed2002

Simvastatin promotes atherosclerotic plaque stability in apoE-deficient mice independently of lipid lowering.

OBJECTIVE: This study sought to determine whether simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has stabilizing effects on vulnerable atherosclerotic plaques that are independent of their lipid-lowering capabilities. METHODS AND RESULTS: Simvastatin (50 mg/kg per day) was administered to 30-week-old apolipoprotein E-deficient mice exhibiting advanced unstable atherosclerotic lesions within the innominate/brachiocephalic artery. Simvastatin was administered in the chow to separate groups of mice for 6, 12, 18, or 24 weeks. Simvastatin significantly increased serum cholesterol after 12, 18, and 24 weeks of treatment. The average cross-sectional area of atherosclerotic lesion increased in the innominate artery after 12 and 24 weeks of treatment, concomitant with the increase in serum cholesterol. However, histological analysis of sections of the innominate artery stained with Movat and von Kossa stains demonstrated a 49% reduction in the frequency of intraplaque hemorrhage and a 56% reduction in the frequency of calcification, both markers of advanced and unstable atherosclerotic plaques. CONCLUSIONS: These data suggest that despite an increase in serum cholesterol and lesion size, simvastatin has stabilizing effects on advanced atherosclerotic lesions.

Animals↗
PubMed2003

Simvastatin modulates expression of the PON1 gene and increases serum paraoxonase: a role for sterol regulatory element-binding protein-2.

BACKGROUND: The HDL-associated enzyme paraoxonase protects LDLs from oxidative stress. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) appear to favorably influence the atherosclerotic process by different mechanisms. The present study examined the influence of simvastatin on paraoxonase expression and serum paraoxonase levels. METHODS AND RESULTS: Simvastatin upregulated in a dose-dependent manner the activity of the promoter of the paraoxonase gene in expression cassettes transfected into HepG2 cells. Upregulation could be blocked by mevalonate and other intermediates of the cholesterol biosynthetic pathway. Simvastatin increased nuclear factors, notably sterol regulatory element-binding protein-2, capable of binding to the paraoxonase promoter; this was also blocked by mevalonate. Sterol regulatory element-binding protein-2 upregulated promoter activity in vitro. Patients treated with statin showed a significant increase in serum concentrations and activities of paraoxonase. CONCLUSIONS: The data indicate that simvastatin can modulate expression in vitro of the antioxidant enzyme paraoxonase and is associated with increased serum paraoxonase concentration and activity. It is consistent with effects of simvastatin treatment, which have the potential to influence beneficially antiatherogenic mechanisms at the HDL level. The study provides evidence for 1 molecular mechanism by which paraoxonase gene expression could be regulated.

Aryldialkylphosphatase↗
PubMed2005

Effects of diet and simvastatin on fatty acid composition in hypercholesterolemic men: a randomized controlled trial.

OBJECTIVE: To explore the separate and combined effects of simvastatin and a low-saturated diet rich in alpha-linolenic acid on serum fatty acids. METHODS AND RESULTS: 120 hypercholesterolemic men were randomly allocated to a habitual diet or dietary treatment group and to receive, in random order, simvastatin 20 mg/d or placebo, each for 12 weeks, in a double-blind manner. Dietary treatment decreased proportions from total fatty acids of palmitic acid (C16:0) by 3.3% (P<0.05), stearic acid (C18:0) by 3.7% (P<0.05) and increased proportions of oleic acid (C18:1n-9) by 4.2% (P<0.01), and alpha-linolenic acid (C18:3n-3) by 29.8% (P<0.001). Simvastatin decreased proportions from total fatty acids of palmitic acid by 2.0% (P<0.01), linoleic acid (C18:2n-6) by 5.3% (P<0.001), and alpha-linolenic acid by 6.8% (P<0.05), and increased proportions of gamma-linolenic acid (C18:3n-6) by 11.1% (P<0.001), dihomo-gamma-linolenic acid (C20:3n-6) by 4.2% (P<0.01), arachidonic acid (C20:4n-6) by 14.2% (P<0.001), and the sum of long-chain polyunsaturated fatty acids (C20-22) by 9.0% (P<0.001). Simvastatin increased ratios of stearic to palmitic, gamma-linolenic to linoleic, and arachidonic to dihomo-gamma-linolenic acid by 7.6%, 17.0%, and 10.0% (P<0.001 for all), respectively, suggesting increased fatty acid elongase and Delta6- and Delta5-desaturase enzyme activities. CONCLUSIONS: Increased formation of long-chain polyunsaturated fatty acids and their metabolites may contribute a substantial part of the pleiotropic effects of simvastatin.

Adult↗
PubMed2006

Suppression of RAGE as a basis of simvastatin-dependent plaque stabilization in type 2 diabetes.

OBJECTIVE: Receptor for advanced glycation end products (AGEs) (RAGE) plays a central role in the process of plaque rupture in diabetic patients. Recently, it has been reported that RAGE may be downregulated by improving glycemic control. In contrast, despite being well known that RAGE may be induced in human vessels in a glucose-independent fashion, also by myeloperoxidase (MPO)-dependent AGE generation, no data exist regarding the possibility of a pharmacological modulation of glucose-independent RAGE generation. Thus, the aim of this study was to characterize the effect of simvastatin on the expression of RAGE and RAGE-dependent plaque-destabilizing genes in human atherosclerotic plaques. METHODS AND RESULTS: Seventy type 2 diabetic patients with asymptomatic carotid artery stenosis (>70%) were randomized to American Heart Association (AHA) step 1 diet plus simvastatin (40 mg/d) or AHA step 1 diet alone for 4 months before endarterectomy. Plaque expression of MPO, AGEs, RAGE, NF-kappaB, COX-2, mPGES-1, matrix metalloproteinase (MMP)-2 and MMP-9, lipid and oxidized LDL (oxLDL) content, procollagen 1, and interstitial collagen was analyzed by immunohistochemistry and Western blot; zymography was used to detect MMP activity. Plaques from the simvastatin group had less (P<0.0001) immunoreactivity for MPO, AGEs, RAGE, p65, COX-2, mPGES-1, MMP-2, and MMP-9, lipids and oxLDL; reduced (P<0.0001) gelatinolytic activity; increased (P<0.0001) procollagen 1 and collagen content; and fewer (P<0.0001) macrophages, T-lymphocytes, and HLA-DR+ cells. Of interest, RAGE inhibition by simvastatin, observed not only in plaque sections but also in plaque-derived macrophages, was reverted by addition of AGEs in vitro. CONCLUSIONS: This study supports the hypothesis that simvastatin inhibits plaque RAGE expression by decreasing MPO-dependent AGE generation. This effect in turn might contribute to plaque stabilization by inhibiting the biosynthesis of PGE2-dependent MMPs, responsible for plaque rupture.

Aged↗
PubMed2000

High dose of simvastatin normalizes postprandial remnant-like particle response in patients with heterozygous familial hypercholesterolemia.

Familial hypercholesterolemia (FH) and disturbances in postprandial lipoprotein metabolism are both associated with premature atherosclerosis. The effect of beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors on plasma cholesterol levels in patients with FH is well established; however, it is not known whether postprandial lipoproteins are also influenced. In this case-controlled intervention study, we investigated the effects of high-dose simvastatin on postprandial lipoproteins. We used a new method to analyze remnant lipoproteins based on the immunoseparation principle (remnant-like particle cholesterol [RLP-C] assay) and the well-established measurement of retinyl ester (RE) analysis in plasma and in the Svedberg flotation unit (Sf)<1000 fraction. Seven heterozygous FH patients and 7 control subjects matched for sex, age, body mass index, triglycerides, and apolipoprotein E genotype were enrolled in the study. An oral vitamin A (RE) fat-loading test was performed at baseline in both groups and after 3 months of high-dose simvastatin (80 mg/d) treatment in the FH patients. Before treatment, FH patients had significantly higher fasting and postprandial concentrations of lipoprotein remnants (plasma RLP-C 42+/-19 mg/dL and area under the RLP-C curve 415+/-82 mg. L(-1). h(-1), respectively) than did control subjects (7+/-3 mg/dL and 101+/-35 mg. L( -1). h(-1), respectively; P<0.05), suggesting a delayed clearance of chylomicron remnant particles in the FH patients. Treatment with simvastatin significantly reduced fasting and postprandial remnant lipoprotein cholesterol concentrations (13+/-3 mg/dL and 136+/-53 mg. L(-1). h(-1), respectively; P<0.05 for both). Postprandial RE in the Sf<1000 fraction, not total RE in plasma, was also significantly higher in FH patients than in control subjects (24+/-10 versus 6.3+/-5.9 mg. L( -1). h(-1), P<0.05), but treatment with simvastatin did not result in improvement of the postprandial RE response, either in the Sf<1000 fraction or in plasma. It is concluded that heterozygous FH patients have increased fasting and postprandial remnant lipoprotein concentrations. Treatment with simvastatin significantly reduced the fasting and postprandial RLP-C concentrations but did not result in improved postprandial RE response.

Apolipoproteins↗
PubMed2002

Low-density lipoprotein level reduction by the 3-hydroxy-3-methylglutaryl coenzyme-A inhibitor simvastatin is accompanied by a related reduction of F2-isoprostane formation in hypercholesterolemic subjects: no further effect of vitamin E.

BACKGROUND: Both statins and vitamin E, by reducing the rate of lipid peroxidation, may interfere with oxidative stress, but the impact of their combination is unknown. METHODS AND RESULTS: We randomized 43 hypercholesterolemic patients (21 men, 22 women, age 63+/-11 years) to either simvastatin, to achieve >20% reduction of total cholesterol, or simvastatin plus 600 mg/d vitamin E for 2 months. Patients were then crossed over to the alternative treatment. Lipid parameters documented patients' compliance to simvastatin, whereas plasma levels of vitamin E documented compliance and absorption of vitamin E. We assessed urinary excretion of the isoprostane 8-iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)) as an in vivo index of oxidative stress at baseline and after each month of therapy. 8-Iso-PGF(2alpha) was significantly reduced by simvastatin, from 361+/-148 pg/mg creatinine (mean+/-SD) at baseline to 239+/-124 pg/mg creatinine after 1 month. The addition of vitamin E did not reduce such levels any further (256+/-125 after 1 month). Linear regression analysis showed a weak inverse relationship of 8-iso-PGF(2alpha) with vitamin E levels but a much stronger relationship with LDL cholesterol (R(2)=0.162; P<0.001). CONCLUSIONS: In hypercholesterolemic patients, LDL cholesterol is a major correlate of oxidative stress. Concomitant with LDL cholesterol reduction, simvastatin causes a drastic reduction of oxidative stress to a level that is not further reduced by the addition of vitamin E. Results of clinical trials with vitamin E may have been hampered by inadequate knowledge of the background level of lipid peroxidation, which is a major determinant of vitamin E bioactivity.

Antioxidants↗
PubMed2003

Simvastatin initiated early after heart transplantation: 8-year prospective experience.

BACKGROUND: Randomized clinical trials have demonstrated that the use of statins in heart transplant patients lowers cholesterol levels and significantly reduces mortality and the development of transplant vasculopathy. The aim of the present study was to test these effects and the safety of statin therapy over an 8-year period. METHODS AND RESULTS: In 1991, a prospective, randomized, unmasked study was initiated to compare the efficacy of simvastatin, started on the fourth postoperative day (n=35), with that of dietary therapy alone (n=37). Because of significantly improved survival and a lower incidence of transplant vasculopathy, most patients in both groups received statins as open-label prescriptions after 4 years. After 8 years, the Kaplan-Meier survival rate was 88.6% in the simvastatin group versus 59.5% in the control group (P<0.006 by log rank; hazard ratio, 0.24; 95% CI, 0.08 to 0.71). Deaths in the simvastatin and control groups were due to transplant vasculopathy (1 versus 4; P<0.2), severe transplant rejection (1 versus 5; P<0.1), malignancies (0 versus 3; P<0.1), and other causes (2 versus 3; P<0.7). The incidence of transplant vasculopathy confirmed by angiography was 24.4% in the simvastatin group versus 54.7% in the control group (P<0.02 by log rank). There was no difference in organ function between the 2 groups. No severe adverse effects of the therapy were observed up to the end of the 8-year observation period. CONCLUSIONS: Simvastatin therapy initiated early after heart transplantation leads to significantly better 8-year survival rates and a significantly lower incidence of transplant vasculopathy without impairment of organ function or severe adverse effects.

Adult↗
PubMed2003

Suppression of the functionally coupled cyclooxygenase-2/prostaglandin E synthase as a basis of simvastatin-dependent plaque stabilization in humans.

BACKGROUND: The clinical benefits of statins are attributed to changes in plaque composition that lead to reduced metalloproteinase (MMP) activity and plaque stabilization. However, the molecular mechanism of this effect is unclear. Recently, we demonstrated enhanced expression of isoforms of inducible cyclooxygenase (COX) and PGE synthase (COX-2/mPGES) in human symptomatic plaque and provided evidence that this is associated with MMP-induced plaque rupture. The aim of this study was to characterize the effect of simvastatin on inflammatory infiltration and the expression of COX-2/mPGES and MMPs in human carotid plaques. METHODS AND RESULTS: Seventy patients with symptomatic carotid artery stenosis were randomized to the American Heart Association Step 1 diet plus simvastatin (40 mg/d) or the American Heart Association Step 1 diet alone for 4 months before endarterectomy. Plaques were subjected to analysis of COX-1, COX-2, mPGES, MMP-2 and MMP-9, lipid and oxidized LDL (oxLDL) content, and collagen content by immunocytochemistry, Western blot, and reverse transcription-polymerase chain reaction, whereas zymography was used to detect MMP activity. Immunocytochemistry was also used to identify CD68+ macrophages, CD3+ T-lymphocytes, smooth muscle cells (SMCs), and HLA-DR+ inflammatory cells. Plaques from the simvastatin group had fewer (P<0.0001) macrophages, T-lymphocytes, and HLA-DR+ cells; less (P<0.0001) immunoreactivity for COX-2/mPGES and MMPs; reduced (P<0.0001) gelatinolytic activity; increased (P<0.0001) collagen content; and reduced (P<0.0001) lipid and oxLDL content. Interestingly, COX-2/mPGES inhibition by simvastatin was completely reversed by mevalonate in vitro. CONCLUSIONS: This study demonstrates that simvastatin decreases inflammation and inhibits COX-2/mPGES expression in plaque macrophages, and this effect in turn may contribute to plaque stabilization by inhibition of MMP-induced plaque rupture.

Aged↗
PubMed2003

Enhanced interleukin-1beta in hypercholesterolemia: effects of simvastatin and low-dose aspirin.

BACKGROUND: This study was aimed at verifying whether activation of platelets might represent a source of interleukin (IL)-1beta levels in hypercholesterolemia. To this purpose, we compared the effects of a short-term treatment with simvastatin or low-dose aspirin on circulating levels of this cytokine. METHODS AND RESULTS: Fifty patients with hypercholesterolemia were randomly allocated to receive an 8-week therapeutic course of simvastatin 20 mg daily (n=25) or aspirin 100 mg daily (n=25). Baseline soluble (s) P-selectin directly correlated with IL-1beta (P<0.0001) and C-reactive protein (CRP) (P<0.05) but not with von Willebrand factor, total cholesterol, or LDL cholesterol levels. Furthermore, sP-selectin (P<0.02) and IL-1beta (P<0.0001) levels were independently related to CRP by multiple regression analysis. Both drugs were associated with comparable, significant reductions in IL-1beta and sP-selectin. Simvastatin, but not aspirin treatment, significantly lowered CRP levels (P<0.05). The change in IL-1beta levels correlated with the change in sP-selectin in patients randomized to either simvastatin (Rho, 0.42; P<0.05) or aspirin (Rho, 0.42; P<0.05). In contrast, the simvastatin-induced change in IL-1beta did not correlate with the change in CRP levels. CONCLUSIONS: This study suggests that platelets might contribute to IL-1beta production in hypercholesterolemia, thus providing an additional link between inflammation and the prothrombotic state in this setting.

Adult↗
PubMed2005

Simvastatin inhibits cigarette smoking-induced emphysema and pulmonary hypertension in rat lungs.

RATIONALE: In cigarette smoking-induced chronic obstructive pulmonary disease, structural and functional derangements are characterized by parenchymal destruction and pulmonary hypertension. Statins are 3-hydroxy-3-methyl-glutaryl-coenzyme-A reductase inhibitors that have been used as lipid-lowering agents. These drugs also have additional pharmacologic properties, including antiinflammation, scavenging reactive oxygen species, restoring endothelial function, and antithrombogenesis, all of which can counteract the harmful effects of cigarette smoking. OBJECTIVE: We performed assays to determine whether simvastatin could attenuate lung damage induced by chronic cigarette smoking in rats. METHODS: In Sprague-Dawley rats exposed to cigarette smoke for 16 weeks, morphologic changes in the lungs and pulmonary arterial pressure were examined. MAIN RESULTS: Simvastatin inhibited lung parenchymal destruction and development of pulmonary hypertension, and also inhibited peribronchial and perivascular infiltration of inflammatory cells and induction of matrix metalloproteinase-9 activity in lung tissue. Simvastatin additionally prevented pulmonary vascular remodeling and the changes in endothelial nitric oxide synthase expression induced by smoking. In human lung microvascular endothelial cells, simvastatin increased expression of endothelial nitric oxide synthase mRNA. CONCLUSIONS: Simvastatin ameliorated the structural and functional derangements of the lungs caused by cigarette smoking, partly by suppressing inflammation and matrix metalloproteinase-9 induction and preventing pulmonary vascular abnormality. These findings indicate that statins may play a role in the treatment of cigarette smoking-induced chronic obstructive pulmonary disease.

Administration, Oral↗
PubMed1998

Suppressive effect of simvastatin on intramural small coronary arterial lesions in cholesterol-fed rabbits.

The aim of this study was to examine the suppressive effect of simvastatin on intramural coronary arterial lesions in cholesterol-fed rabbits. In one experiment, six groups of rabbits were fed laboratory chow alone or with added 0.1%, 0.2%, 0.3%, 0.5% or 1.0% cholesterol for 16 weeks. In another experiment, four groups of rabbits were fed a 0.5% cholesterol diet and treated with simvastatin at 1, 3, or 5 mg/kg/day or placebo. In each rabbit, the levels of serum total cholesterol (TC) were determined at 1-week intervals to calculate the integrated values. The lesion induction ratio was defined as the ratio of intramural coronary arteries 50-150 microm in diameter with arterial lipoidosis to the total number of arteries of the same diameter. In the two experiments, there were positive correlations between the lesion induction ratio and integrated TC (r=0.785, P<0.0001 and r=0.763, P<0.0001, respectively). The slopes of the regression lines for integrated TC obtained in the two experiments were similar, but the lesion induction ratio in the simvastatin-treated group was always lower, by about 14%, in comparison with that in the non-simvastatin-treated group. These findings suggest that simvastatin induces lesion reduction not only by reducing the levels of circulating cholesterol but also by directly suppressing the development of lipoidosis.

Animals↗
PubMed2005

The effect of high-dose simvastatin on triglyceride-rich lipoprotein metabolism in patients with type 2 diabetes mellitus.

Statins decrease triglycerides (TGs) in addition to decreasing low density lipoprotein-cholesterol. Although the mechanism for the latter effect is well understood, it is still unclear how TG decrease is achieved with statin therapy. Because hypertriglyceridemia is common in obese patients with type 2 diabetes mellitus, we studied triglyceride-rich lipoprotein triglyceride (TRL-TG) turnover in 12 such subjects using stable isotopically labeled glycerol. The diabetic subjects were studied after 12 weeks of placebo and after a similar course of therapy with simvastatin (80 mg daily) in a single-blind design. The results were compared with those from six nonobese nondiabetic control subjects. Simvastatin therapy reduced serum TGs by 35% in the diabetic subjects. Compared with the control subjects, TRL-TG secretion was almost 2-fold higher in the diabetic subjects (45.4 +/- 4.9 vs. 24.4 +/- 1.9 micromol/min; P < 0.002) and was unaffected by simvastatin therapy. However, TRL-TG clearance was significantly increased in the diabetic subjects during simvastatin treatment compared with placebo (0.25 +/- 0.03 vs. 0.16 +/- 0.02 pools/h; P < 0.002). This change was accompanied by a 49% increase in preheparin plasma lipase activity (P < 0.03) and a 21% increase in postheparin LPL activity (P < 0.01). Together, these findings provide strong evidence that the effect of statins on serum TGs is related to an increase in LPL activity, resulting in accelerated delipidation of TRL particles. The effect of high-dose simvastatin on triglyceride-rich lipoprotein metabolism in patients with type 2 diabetes mellitus.

Adult↗
PubMed2006

The molecular mechanisms underlying the reduction of LDL apoB-100 by ezetimibe plus simvastatin.

The combination of ezetimibe, an inhibitor of Niemann-Pick C1-like 1 protein (NPC1L1), and an HMG-CoA reductase inhibitor decreases cholesterol absorption and synthesis. In clinical trials, ezetimibe plus simvastatin produces greater LDL-cholesterol reductions than does monotherapy. The molecular mechanism for this enhanced efficacy has not been defined. Apolipoprotein B-100 (apoB-100) kinetics were determined in miniature pigs treated with ezetimibe (0.1 mg/kg/day), ezetimibe plus simvastatin (10 mg/kg/day), or placebo (n = 7/group). Ezetimibe decreased cholesterol absorption (-79%) and plasma phytosterols (-91%), which were not affected further by simvastatin. Ezetimibe increased plasma lathosterol (+65%), which was prevented by addition of simvastatin. The combination decreased total cholesterol (-35%) and LDL-cholesterol (-47%). VLDL apoB pool size decreased 26%, due to a 35% decrease in VLDL apoB production. LDL apoB pool size decreased 34% due to an 81% increase in the fractional catabolic rate, both of which were significantly greater than monotherapy. Combination treatment decreased hepatic microsomal cholesterol (-29%) and cholesteryl ester (-65%) and increased LDL receptor (LDLR) expression by 240%. The combination increased NPC1L1 expression in liver and intestine, consistent with increased SREBP2 expression. Ezetimibe plus simvastatin decreases VLDL and LDL apoB-100 concentrations through reduced VLDL production and upregulation of LDLR-mediated LDL clearance.

ATP-Binding Cassette Transporters↗
PubMed2003

Effects of bezafibrate and simvastatin on endothelial activation and lipid peroxidation in hypercholesterolemia: evidence of different vascular protection by different lipid-lowering treatments.

Hypercholesterolemia is combined with enhanced lipid peroxidation, which can promote atherogenesis by inducing endothelial adhesion molecule expression. Statins may protect vascular endothelium in hypercholesterolemia by reducing enhanced plasma levels of low-density lipoprotein and decreasing oxidative stress. Herein, we describe increased circulating levels of soluble intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin and total 8-iso-prostaglandin F(2 alpha) (8-iso-PGF(2 alpha)) concentrations, as indexes of endothelial activation and lipid peroxidation, respectively, in 67 hypercholesterolemic patients compared with 32 normocholesterolemic subjects. Significant cholesterol reductions were achieved in hypercholesterolemic patients after 6 months under either simvastatin (40 mg/d) or bezafibrate (800 mg/d) treatment, given according to a randomized double-blind trial. Simvastatin but not bezafibrate simultaneously reduced soluble adhesin and total 8-iso-PGF(2 alpha) concentrations also. Vitamin E supplementation (400 IU/d) further reduced indexes of endothelial activation and lipid peroxidation in simvastatin-treated patients and significantly reduced the above indexes in bezafibrate-treated patients. Changes in circulating soluble adhesion molecule levels were directly correlated with changes in total 8-iso-PGF(2 alpha) concentrations in simvastatin-treated patients also receiving vitamin E supplementation. All together, our data demonstrated that hypercholesterolemia was combined with endothelial activation and lipid peroxidation, which were efficaciously counteracted by simvastatin but not bezafibrate treatment. Thus, a different vascular protection can be achieved by different lipid-lowering treatments.

Adult↗
PubMed2006

Direct demonstration of an antiinflammatory effect of simvastatin in subjects with the metabolic syndrome.

CONTEXT: Metabolic syndrome (MS) is characterized by low-grade inflammation and confers an increased risk for cardiovascular disease. Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) reduce cardiovascular events in MS patients. There is a paucity of data examining the effect of statins on inflammation in MS. OBJECTIVE: We aimed to test the effect of simvastatin (40 mg/d) compared with placebo on biomarkers of inflammation [high-sensitivity C-reactive protein (hsCRP) and monocytic cytokines TNF, IL-6, and IL-1] in MS subjects. DESIGN AND PATIENTS: We conducted a randomized, double-blind, placebo-controlled study at the University of California, Davis, Medical Center. PARTICIPANTS: Participants were subjects with MS. INTERVENTION: Simvastatin (40 mg/d) or placebo was administered for 8 wk. METHODS AND RESULTS: The hsCRP levels were assayed using a high-sensitivity immunoassay. Monocyte cytokines were assayed by ELISA after activation with lipopolysaccharide. Simvastatin therapy significantly decreased hsCRP levels in MS subjects compared with placebo (P < 0.0005) and resulted in a significant reduction in plasma and lipopolysaccharide-activated monocytic release of IL-6 and TNF (P < 0.025). Simvastatin therapy significantly decreased nuclear factor-kappaB and increased Akt activity in MS subjects compared with placebo. To gain mechanistic insights, human monocytes were pretreated with lovastatin with and without mevalonate or a phosphatidyl-3-kinase inhibitor or Rho kinase inhibitor. Lovastatin significantly decreased Rho kinase and nuclear factor-kappaB activity, significantly increased Akt activity, and resulted in decreased monocyte IL-6 levels; these effects were reversed with mevalonate and geranylgeranyl pyrophosphate, indicating direct effects of statins on protein prenylation. CONCLUSIONS: Thus, we show a direct antiinflammatory effect of simvastatin therapy in MS. These findings could partly explain the benefit of statin therapy in these patients.

Adult↗
PubMed2004

Simvastatin, an HMG-CoA reductase inhibitor, reduced the expression of matrix metalloproteinase-9 (Gelatinase B) in osteoblastic cells and HT1080 fibrosarcoma cells.

MMP-9 or Gelatinase B, a member of the matrix metalloproteinase family (MMPs), plays important roles in physiological events such as tissue remodeling and in pathological processes that lead to destructive bone diseases, including osteoarthritis and periodontitis. In addition to its effect on the increase of total bone mass, statin (an HMG-CoA reductase inhibitor) suppresses the expression of MMPs. In this study, we proposed that simvastatin reduces MMP-9 expression in osteoblasts and HT1080 fibrosarcoma cell line. Gelatin zymography, Western blot analysis and reverse transcriptase-PCR were used to investigate the effects of simvastatin on MMP-9 in primary calvaria cells, U2-OS osteosarcoma cells, and HT1080 fibrosarcoma cells. The results from gelatin zymography and Western blot analysis revealed that simvastatin suppressed MMP-9 activity in these cells in concentration- and time-dependent manners. The effective concentrations of simvastatin were 100 - 500 nM, 5 - 15 microM, and 2.5 - 10 microM in primary calvaria, U2-OS, and HT1080 cells, respectively. Collectively, these results suggest that simvastatin is a potent drug for inhibition of MMP-9 expression in osteoblastic cells and HT1080 fibrosarcoma cells.

Animals↗