Statins and their role in vascular protection

Abstract

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.

Resveratrol Inhibits Monocytic Cell Chemotaxis to MCP-1 and Prevents Spontaneous Endothelial Cell Migration Through Rho Kinase-Dependent Mechanism

“…In contrast to specific ROCK inhibitors, little effect on the inhibition of endothelial migration by resveratrol was observed when the cells were treated with simvastatin. This was not unexpected, as the inhibition of protein isoprenylation by statins affects, apart from RhoA, several other Rho GTPases essential for cell migration 17) , e.g. Rac, which affects lamellipodia formation, or Cdc42 responsible for filopodia extension.…”

Induction of the Cytoprotective Enzyme Heme Oxygenase-1 by Statins Is Enhanced in Vascular Endothelium Exposed to Laminar Shear Stress and Impaired by Disturbed Flow

“…The observation that beneficial actions of statins on vascular function are detectable prior to any fall in serum cholesterol, extend to normocholesterolemic patients and exceed those of other lipid-lowering drugs despite comparable falls in total cholesterol (2,3), suggest the existence of low density lipoprotein-cholesterol-independent effects (4,5). Judging from in vitro studies, these may include immunomodulatory, antiinflammatory, anti-adhesive, anti-thrombotic, and cytoprotective actions (6).…”

“…Judging from in vitro studies, these may include immunomodulatory, antiinflammatory, anti-adhesive, anti-thrombotic, and cytoprotective actions (6). However, the experimental work demonstrating these pleiotropic effects has predominantly used statin concentrations exceeding those achieved by therapeutic dosing, raising questions concerning clinical relevance (4).…”

Beyond the Lipid-lowering Effects of Statins: Renal Effects

“…But are also known to create inhibitory action on angiogenesis in high doses of these drugs. In addition, statins cause significant reduction in thrombotic events including major cerebral ischemia and stroke risk with increased fibrinolytic extracellular activity; decrease expression of tissue factor, and decrease platelet activation (21,22) .…”