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Clinical Science (2003) 105, (251–266) (Printed in Great Britain)

Review article

Statins and their role in vascular protection

Justin C. MASON

British Heart Foundation Cardiovascular Medicine Unit, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, U.K.

Key words: cytoprotection, endothelium, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, inflammation, pleiotropic effect, statins.

Abbreviations: apo, apolipoprotein; Ang II, angiotensin II; AT₁, Ang II type 1 receptor; CHD, coronary heart disease; CRP, C-reactive protein; CVA, cerebrovascular accident; DAF, decay-accelerating factor; Ecto-5´-Nu, ecto-5´-nucleotidase; EC, endothelial cell; EPC, endothelial progenitor cell; FPP, farnesylpyrophosphate; GGPP geranylgeranylpyrophosphate; HDL, high-density lipoprotein; HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; HUVEC, human umbilical vein EC; ICAM-1, intercellular cell-adhesion molecule-1; IFNg, interferon g; IL, interleukin; LDL, low-density lipoprotein; LFA-1, leucocyte function antigen-1; MMP, matrix metalloproteinase; NF-kB, nuclear factor kB; NO, nitric oxide; eNOS, endothelial NO synthase; PI3K, phosphinositide 3-kinase; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SMC, smooth muscle cell; STAT, signal transducer of transcription; TNFa, tumour necrosis factor a; TF, tissue factor; VCAM-1, vascular cell-adhesion molecule-1; VSMC, vascular SMC.

Correspondence: Dr Justin Mason (e-mail justin.mason@imperial.ac.uk).

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.

Received 23 April 2003/28 May 2003; accepted 6 June 2003

Published as Immediate Publication 6 June 2003, DOI 10.1042/CS20030148

© 2003 The Biochemical Society