Effect of Simvastatin Therapy on Cell Membrane Cholesterol Content and Membrane Function as Assessed by Polymorphonuclear Cell NADPH Oxidase Activity

Day, A.; Bellavía, S. L.; Jones, Owen; Stansbie, D.

doi:10.1177/000456329703400308

Cited by 28 publications

(17 citation statements)

References 26 publications

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“…Bokoch and Prossnitz (1992) showed that lovastatin (0.4-10 µM) decreases formyl-methionyl-leucylphenylalanine-and phorbol ester-induced superoxide radical generation by HL-60 cells (human promyelocytic cell line differentiated to macrophages). A decrease in membrane NAD(P)H oxidase activity of polymorphonuclear leukocytes was observed in hyperlipidemic humans after a 6-week treatment with simvastatin (Day et al 1997). Shishehbor et al (2003b) demonstrated that atorvastatin (10 mg/day for 12 weeks) decreases serum levels of chlorotyrosine and dityrosine that are formed specifically in a myeloperoxidase-dependent manner, suggesting that statin treatment reduces ROS generation by myeloperoxidasecontaining inflammatory cells.…”

Section: Effect On Inflammatory Cellsmentioning

confidence: 98%

Statins and Modulation of Oxidative Stress

Bełtowski

2005

Toxicology Mechanisms and Methods

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Statins inhibit the activity of a rate-limiting enzyme in cholesterol biosynthesis, converting 3-hydroxy 3-methylglutaryl coenzyme A to mevalonate, and are widely used in the treatment of cardiovascular diseases. Statins decrease the synthesis of cholesterol and other nonsteroid isoprenoids originating from mevalonate, such as farnesyl- and geranylgeranylpyrophosphate, dolichol, and ubiquinone. Recent studies indicate that the beneficial effect of statins on cardiovascular risk also occurs in persons with normal plasma cholesterol because of the pleiotropic cholesterol-independent activities of statins. Among these effects, modulation of oxidative stress is one of the most important. Statins reduce the generation of reactive oxygen species by vascular NAD(P)H oxidase, inhibit the respiratory burst of phagocytes, antagonize the prooxidant effect of angiotensin II and endothelin-1, and increase the synthesis of vascular nitric oxide. Some statins and their metabolites posses direct free radical scavenging activity. The antioxidant effect of statins contributes to inhibition of atherogenesis, stabilization of atherosclerotic plaque, inhibition of myocardial hypertrophy and remodeling, and modulation of vascular tone. However, the prooxidant effect of statins resulting from the inhibition of ubiquinone synthesis has also been reported in some experimental models. This effect may contribute to side effects of statins, such as myopathy and hepatotoxicity.

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Section: Effect On Inflammatory Cellsmentioning

confidence: 98%

Statins and Modulation of Oxidative Stress

Bełtowski

2005

Toxicology Mechanisms and Methods

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“…The ability to scavenge oxygen-derived free radicals is shared by many statins, including simvastatin [141], fluvastatin [142], atorvastatin, pravastatin and cerivastatin [143], and has been demonstrated in a variety of cell types, including macrophages, neutrophils, VSMCs and ECs [141,144]. The functional effects of reduced oxidative stress are varied.…”

Section: Antioxidant Effects Of Statinsmentioning

confidence: 99%

Statins and their role in vascular protection

Mason

2003

Clinical Science

107

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The statins reduce cholesterol synthesis through inhibition of HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase and are widely prescribed for hyperlipidaemia to reduce the risk of atherosclerotic complications. The beneficial effect of lipid lowering by statins in the treatment of coronary heart disease has been demonstrated in large clinical trials. However, statins appear to have additional benefits on vascular function above and beyond their lipid lowering effects. Through inhibition of L-mevalonate synthesis, statins also prevent the synthesis of isoprenoid intermediates, including farnesylpyrophosphate and geranylgeranylpyrophosphate. Isoprenylation is important in the post-translational modification of a variety of proteins, including the small GTPases Rho, Rac and Ras, and hence plays an integral role in cellular signalling. Moreover, interference with isoprenylation underlies many of the beneficial actions of the statins on vascular endothelium, which include increased endothelial nitric oxide synthase expression, pro-angiogenic effects, increased fibrinolytic activity, immunomodulatory and anti-inflammatory actions, including increased resistance to complement. This has led to interest in the use of this class of drugs outside the realm of cardiovascular disease.

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“…In addition to de novo biosynthesis, mammalian cells can take up cholesterol from the extracellular milieu. Exposure to elevated cholesterol levels both in vivo and in vitro enhances cholesterol abundance within the plasma membrane of neutrophils and other blood cells [39][40][41][42]. These findings, in conjunction with the wealth of evidence demonstrating the influence of the extracellular cholesterol levels on neutrophil activity, point to membrane cholesterol enrichment as a potential link between hypercholesterolemia and chronic neutrophil activity.…”

Section: The Influence Of Cholesterol On Neutrophil Activitymentioning

confidence: 77%

“…Lipoproteins (e.g., LDL) in the blood plasma are positioned in close proximity to the circulating blood cells. Conditions that elevate cholesterol-enriched lipoprotein levels may thus favor cholesterol transport into the membranes of these blood cells [39,42]. In the laboratory, cyclodextrin derivatives (e.g., methyl--cyclodextrin or MCD), synthetic cholesterol carrier molecules, are commonly used to alter membrane cholesterol abundance.…”

Section: Transport Of Extracellular Cholesterol Into the Plasma Membranementioning

confidence: 99%