Statins and their role in vascular protection.
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.
Mason
Justin C
JC
British Heart Foundation Cardiovascular Medicine Unit, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK. justin.mason@imperial.ac.uk
D000368:Aged; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D002784:Cholesterol / Q000096:biosynthesis; D003165:Complement System Proteins / Q000502:physiology; D003327:Coronary Disease / Q000517:prevention & control*; D016207:Cytokines / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism*; D005342:Fibrinolysis; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D009569:Nitric Oxide / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic; D013927:Thrombosis / Q000378:metabolism
D000975:Antioxidants; D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009569:Nitric Oxide; D003165:Complement System Proteins; D002784:Cholesterol