Effects of simvastatin on plasma lipid, lipoprotein and apolipoprotein concentrations in hypercholesterolaemia.

Olsson AG.

Department of Internal Medicine, Linkoping University Hospital, Sweden.

The effect of 24 weeks of treatment with simvastatin, a new HMG coenzyme A reductase inhibitor (dosages of 20 and 40 mg day-1) on serum lipid, lipoprotein and apolipoprotein A-I and B concentrations as well as safety parameters and subjective side effects were studied in 11 patients with familial (FH) and 10 patients with polygenic hypercholesterolaemia (P-HC). The effects on plasma lipoprotein and apolipoprotein concentrations had already been achieved after four weeks in both groups and then remained during the study. In FH, mean fasting plasma total cholesterol concentration decreased from 10.51 to 6.71 mmol l-1 (36%), and in P-HC from 6.55 to 4.54 mmol l-1 (31%) at 24 weeks (P less than 0.001). Mean plasma low density lipoprotein (LDL) cholesterol concentrations also decreased, in FH from 8.87 to 5.05 mmol l-1 (43%) and in P-HC from 4.97 to 3.12 mmol l-1 (37%) at 24 weeks (P less than 0.001). Furthermore, apolipoprotein B concentrations decreased significantly from 2.21 to 1.57 g l-1 (29%) (less than 0.001) in FH and from 1.53 to 1.09 g l-1 (29%) (P less than 0.01) in P-HC. Plasma high density lipoprotein (HDL) cholesterol increased in both FH and P-HC during treatment. Increases were seen in both the subfractions HDL2 and HDL3. Simvastatin was well tolerated. No serious clinical or laboratory adverse effects were observed. It is concluded that 24 weeks of treatment with simvastatin in doses up to 40 mg day-1 effectively reduces plasma total and LDL cholesterol concentrations without causing subjective or significant objective side effects. Thus, simvastatin may be of great interest in future studies for prevention of coronary heart disease due to hypercholesterolaemia.

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Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury.

Garcia JG.

Center for Translational Respiratory Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. drgarcia jhmi.edu

Therapies to limit the life-threatening vascular leak observed in patients with acute lung injury (ALI) are currently lacking. We explored the effect of simvastatin, a 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor that mediates endothelial cell barrier protection in vitro, in a murine inflammatory model of ALI. C57BL/6J mice were treated with simvastatin (5 or 20 mg/kg body wt via intraperitoneal injection) 24 h before and again concomitantly with intratracheally administered LPS (2 microg/g body wt). Inflammatory indexes [bronchoalveolar lavage (BAL) myeloperoxidase activity and total neutrophil counts assessed at 24 h with histological confirmation] were markedly increased after LPS alone but significantly reduced in mice that also received simvastatin (20 mg/kg; approximately 35-60% reduction). Simvastatin also decreased BAL albumin (approximately 50% reduction) and Evans blue albumin dye extravasation into lung tissue (100%) consistent with barrier protection. Finally, the sustained nature of simvastatin-mediated lung protection was assessed by analysis of simvastatin-induced gene expression (Affymetrix platform). LPS-mediated lung gene expression was significantly modulated by simvastatin within a number of gene ontologies (e.g., inflammation and immune response, NF-kappaB regulation) and with respect to individual genes implicated in the development or severity of ALI (e.g., IL-6, Toll-like receptor 4). Together, these findings confirm significant protection by simvastatin on LPS-induced lung vascular leak and inflammation and implicate a potential role for statins in the management of ALI.

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Simvastatin inhibits growth factor expression and modulates profibrogenic markers in lung fibroblasts.

Spiteri MA.

Lung Research, Institute of Science and Technology in Medicine, University Hospital of North Stafforshire/Keel University, School of Postgraduate Medicine, Thornburrow Drive, Hartshill, Stoke on Trent ST4 7NQ, UK. keira_watts yahoo.co.uk

Simvastatin is best known for its antilipidemic action and use in cardiovascular disease due to its inhibition of 3-hydroxy-3-methylglutaryl CoenzymeA (HMG CoA) reductase, a key enzyme in the cholesterol synthesis pathway. Inhibition of biological precursors in this pathway also enables pleiotrophic immunomodulatory and anti-inflammatory capabilities, including modulation of growth factor expression. Connective tissue growth factor (CTGF) and persistent myofibroblast formation are major determinants of the aggressive fibrotic disease, idiopathic pulmonary fibrosis (IPF). In this study we used human lung fibroblasts derived from healthy and IPF lungs to examine Simvastatin effects on CTGF gene and protein expression, analyzed by RT-PCR and ELISA, respectively. Simvastatin significantly inhibited (P < 0.05) CTGF gene and protein expression, overriding the induction by transforming growth factor-beta1, a known potent inducer of CTGF. Such Simvastatin suppressor action on growth factor interaction was reflected functionally on recognized phenotypes of fibrosis. alpha-smooth muscle actin expression was downregulated and collagen gel contraction reduced by 4.94- and 7.58-fold in IMR90 and HIPF lung fibroblasts, respectively, when preconditioned with 10 microM Simvastatin compared with transforming growth factor-beta1 treatment alone after 24 h. Our data suggest that Simvastatin can modify critical determinants of the profibrogenic machinery responsible for the aggressive clinical profile of IPF, and potentially prevents adverse lung parenchymal remodeling associated with persistent myofibroblast formation.

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Reduction of cerebral infarction in stroke-prone spontaneously hypertensive rats by statins associated with amelioration of oxidative stress.

Abe K.

Department of Neurology, Graduate School of Medicine and Dentistry, Okayama University, Okayama, Japan.

BACKGROUND AND PURPOSE: This study aimed to clarify the effect of statins on spontaneous stroke and to examine the antioxidative effect in artificial transient middle cerebral artery occlusion (tMCAO). METHODS: Stroke-prone spontaneous hypertensive rats (SHR-SP) were treated with pitavastatin, atorvastatin, simvastatin, or vehicle for 4 weeks. Physiological parameters, serum lipids, and infarct volumes were examined. The markers for oxidative stresses on lipids and DNA were immunohistochemically detected in vehicle-treated or simvastatin-treated SHR-SP with tMCAO. RESULTS: Atorvastatin and simvastatin decreased infarct volumes, with simvastatin most effective. Simvastatin significantly reduced immunoreactivities for oxidative stress markers for lipids and DNA in neurons after tMCAO. CONCLUSIONS: The results suggest that the antioxidative properties of statins may be implicated in their beneficial effects against neuronal damage in cerebral ischemia.

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Atheroma stabilizing effects of simvastatin due to depression of macrophages or lipid accumulation in the atheromatous plaques of coronary plaque-prone WHHL rabbits.

Ito T.

Institute for Experimental Animals, Kobe University School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. ieakusm med.kobe-u.ac.jp

Clinical studies showed that both hydrophilic and lipophilic statins reduce coronary events although in vitro studies demonstrated that lipophilic statins inhibited proliferation of arterial smooth muscle cells. Therefore, we examined whether lipophilic simvastatin reduces smooth muscle cells in atheromatous plaque and how simvastatin affects stability of atheroma in vivo. Coronary atherosclerosis-prone WHHLCA rabbits aged 10 months were given simvastatin (15 mg/kg) orally for 52 weeks and examined the serum lipid levels, plasma drug concentration, and aortic and coronary atherosclerosis. Compared to the placebo group, the plasma cholesterol levels decreased by about 20%. In the simvastatin group, the lipid component (macrophages+extracellular lipids) was decreased in the coronary and aortic atheroma, despite no decrease in the fibromuscular components. Consequently, the frequency of vulnerable plaque decreased. In the coronary plaque of the simvastatin group, PCNA-positive cells (which appeared to be macrophages) of the plaques decreased but the TUNEL-positive cells did not show significant change. Finally, fully differentiated smooth muscle cells increased in the aortic lesions of the simvastatin group. In conclusion, our results suggest that simvastatin did not depress the fibromuscular components in atheromatous plaques and the plaque-stabilizing effects were due to the reduction of macrophages/lipid deposits.

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Simvastatin attenuates expression of cytokine-inducible nitric-oxide synthase in embryonic cardiac myoblasts.

Geng YJ.

Institute of Cardiology and Center of Excellence on Aging, G. d'Annuzio Univeristy, Chieti, Italy.

Cardiac stem cells or myoblasts are vulnerable to inflammatory stimulation in hearts with infarction or ischemic injury. Widely used for the prevention and treatment of atherosclerotic heart disease, the cholesterol-lowering drugs statins may exert anti-inflammatory effects. In this study, we examined the impact of inhibition of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase with simvastatin on the expression of inducible nitric-oxide synthase (iNOS) in embryonic cardiac myoblasts stimulated with the proinflammatory cytokines, interleukin-1 or tumor necrosis factor. Treatment with simvastatin significantly reduced the levels of iNOS mRNA and protein in cytokine-treated rat H9c2 cardiac embryonic myoblasts. Addition of the HMG-CoA reductase product, L-mevalonate, and the by-product of cholesterol synthesis, geranylgeranyl pyrophosphate, could reverse the statin inhibitory effect on iNOS expression. Simvastatin treatment lowered the Rho GTPase activities, whereas the Rho-associated kinase inhibitor Y27632 partially blocked the statin inhibitory effect on nitrite production in the cytokine-treated H9c2 cells. Treatment with simvastatin led to inactivation of NF-kappaB by elevation of the NF-kappaB inhibitor IkappaB and reduction of the NF-kappaB nuclear contents in the cytokine-stimulated H9c2 cells. Hence, treatment with simvastatin can attenuate iNOS expression and NO synthesis in cytokine-stimulated embryonic cardiac myoblasts. The statin inhibitory effect may occur through isoprenoid-mediated intracellular signal transduction, which involves several key signal proteins, such as Rho kinase and IkappaB/NF-kappaB. These data suggest that statin therapy may protect the cardiac myocyte progenitors against the cytotoxicity of cytokine-induced high output of NO production in infarcted or ischemic hearts with inflammation.

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