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Beyond lipid-lowering: effects of statins on endothelial nitric oxide

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Abstract

Endothelial dysfunction is now recognised as an important process in the pathogenesis of atherosclerosis. Nitric oxide (NO) release by the endothelium regulates blood flow, inflammation and platelet aggregation, and consequently its disruption during endothelial dysfunction can decrease plaque stability and encourage the formation of atherosclerotic lesions and thrombi. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) are often utilised in the prevention of coronary heart disease due to their efficacy at lowering lipid levels. However, statins may also prevent atherosclerotic disease by non-lipid or pleiotropic effects, for example, improving endothelial function by promoting the production of NO. There are various mechanisms whereby statins may alter NO release, such as inhibiting the production of mevalonate and important isoprenoid intermediates, thereby preventing the isoprenylation of the small GTPase Rho, which negatively regulates the expression of endothelial nitric oxide synthase (eNOS). Furthermore, statins may also increase eNOS activity via post-translational activation of the phosphatidylinositol 3-kinase/protein kinase Akt (PI3 K/Akt) pathway and/or through an interaction with the molecular chaperone heat-shock protein 90 (HSP90). Data suggest that statins may vary in their efficacy for enhancing the release of NO, and the mechanisms dictating these differences are not yet clear. By increasing NO production, statins may interfere with atherosclerotic lesion development, stabilise plaque, inhibit platelet aggregation, improve blood flow and protect against ischaemia. Therefore, the ability of statins to improve endothelial function through the release of NO may partially account for their beneficial effects at reducing the incidence of cardiovascular events.

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Acknowledgements

Thanks to G. Allcock for editorial assistance in the preparation of this manuscript. U.L. received financial support from and has been a speaker for AstraZeneca, Bayer, MSD, Novartis, Pfizer and Sankyo. U.L.'s research was supported by the Deutsche Forschungsgemeinschaft and the Universität des Saarlandes.

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  1. Medizinische Klinik und Poliklinik der Universität des Saarlandes, Innere Medizin III, 66421 , Homburg/Saar, Germany

    Ulrich Laufs

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Laufs, U. Beyond lipid-lowering: effects of statins on endothelial nitric oxide. Eur J Clin Pharmacol 58, 719–731 (2003). https://doi.org/10.1007/s00228-002-0556-0

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