Pleiotropic Effects of Statins

Overview

Journal Annu Rev Pharmacol Toxicol

Publisher Annual Reviews

Specialties Pharmacology
Toxicology

Date 2005 Apr 12

PMID 15822172

Citations 588

Authors

James K Liao

Ulrich Laufs

Affiliations

Soon will be listed here.

Abstract

Statins are potent inhibitors of cholesterol biosynthesis. In clinical trials, statins are beneficial in the primary and secondary prevention of coronary heart disease. However, the overall benefits observed with statins appear to be greater than what might be expected from changes in lipid levels alone, suggesting effects beyond cholesterol lowering. Indeed, recent studies indicate that some of the cholesterol-independent or "pleiotropic" effects of statins involve improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response. Furthermore, statins have beneficial extrahepatic effects on the immune system, CNS, and bone. Many of these pleiotropic effects are mediated by inhibition of isoprenoids, which serve as lipid attachments for intracellular signaling molecules. In particular, inhibition of small GTP-binding proteins, Rho, Ras, and Rac, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in mediating the pleiotropic effects of statins.

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References

Wang S, Tsai Y, Jiang M, Tseng Y . Studies on the function of rho A protein in cardiac myofibrillogenesis. J Cell Biochem. 1997; 66(1):43-53. View

Torzewski J, BOWYER D, Waltenberger J, Fitzsimmons C . Processes in atherogenesis: complement activation. Atherosclerosis. 1997; 132(2):131-8. DOI: 10.1016/s0021-9150(97)00100-7. View

Van Aelst L, DSouza-Schorey C . Rho GTPases and signaling networks. Genes Dev. 1997; 11(18):2295-322. DOI: 10.1101/gad.11.18.2295. View

Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T . Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature. 1997; 389(6654):990-4. DOI: 10.1038/40187. View

Bales K, Verina T, Dodel R, Du Y, Altstiel L, Bender M . Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat Genet. 1997; 17(3):263-4. DOI: 10.1038/ng1197-263. View

Harrison D . Cellular and molecular mechanisms of endothelial cell dysfunction. J Clin Invest. 1997; 100(9):2153-7. PMC: 508409. DOI: 10.1172/JCI119751. View

Laufs U, Fata V, Liao J . Inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase blocks hypoxia-mediated down-regulation of endothelial nitric oxide synthase. J Biol Chem. 1998; 272(50):31725-9. DOI: 10.1074/jbc.272.50.31725. View

Katsumata N, Shimokawa H, Seto M, Kozai T, Yamawaki T, Kuwata K . Enhanced myosin light chain phosphorylations as a central mechanism for coronary artery spasm in a swine model with interleukin-1beta. Circulation. 1998; 96(12):4357-63. DOI: 10.1161/01.cir.96.12.4357. View

Hall A . Rho GTPases and the actin cytoskeleton. Science. 1998; 279(5350):509-14. DOI: 10.1126/science.279.5350.509. View

10.

Libby P, Sukhova G, Lee R, Liao J . Molecular biology of atherosclerosis. Int J Cardiol. 1998; 62 Suppl 2:S23-9. DOI: 10.1016/s0167-5273(97)00238-6. View

11.

Laufs U, La Fata V, Plutzky J, Liao J . Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation. 1998; 97(12):1129-35. DOI: 10.1161/01.cir.97.12.1129. View

12.

Kjekshus J, Pedersen T, Olsson A, Faergeman O, Pyorala K . The effects of simvastatin on the incidence of heart failure in patients with coronary heart disease. J Card Fail. 1998; 3(4):249-54. DOI: 10.1016/s1071-9164(97)90022-1. View

13.

. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation. 1998; 97(15):1440-5. DOI: 10.1161/01.cir.97.15.1440. View

14.

Downs J, Clearfield M, Weis S, Whitney E, Shapiro D, Beere P . Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998; 279(20):1615-22. DOI: 10.1001/jama.279.20.1615. View

15.

Perez-Sala D, Hernandez G, Diaz C, Lamas S . Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest. 1998; 101(12):2711-9. PMC: 508862. DOI: 10.1172/JCI1500. View

16.

Braun-Dullaeus R, Mann M, Dzau V . Cell cycle progression: new therapeutic target for vascular proliferative disease. Circulation. 1998; 98(1):82-9. DOI: 10.1161/01.cir.98.1.82. View

17.

Endres M, Laufs U, Huang Z, Nakamura T, Huang P, Moskowitz M . Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci U S A. 1998; 95(15):8880-5. PMC: 21171. DOI: 10.1073/pnas.95.15.8880. View

18.

Crouse 3rd J, Byington R, Furberg C . HMG-CoA reductase inhibitor therapy and stroke risk reduction: an analysis of clinical trials data. Atherosclerosis. 1998; 138(1):11-24. DOI: 10.1016/s0021-9150(98)00014-8. View

19.

Laufs U, Liao J . Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem. 1998; 273(37):24266-71. DOI: 10.1074/jbc.273.37.24266. View

20.

Ridker P, Rifai N, Pfeffer M, Sacks F, Moye L, Goldman S . Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1998; 98(9):839-44. DOI: 10.1161/01.cir.98.9.839. View