Emerging mechanisms for secondary cardioprotective effects of statins
Authors: S Miller
Journal: Cardiovascular Research (2001)

See article by Li et al. [11] ( pages 130 -135) in thisobservations noting these secondary statin effects were issue.correct; however, the mechanisms responsible have only recently begun to come to light.In this issue of Cardiovascular Research, Li et al. [11] demonstrate that 1. Introduction simvastatin and atorvastatin are able to modulate the effects of oxidized-low density lipoprotein (LDL) on LOX-A widely accepted risk factor for the development of 1 expression and protein kinase B (PKB) activity.Their coronary artery disease is an elevated level of plasma results indicate that these statins inhibit oxidized-LDLcholesterol.Early on, it was recognized that inhibition of mediated increases in LOX-1 expression, as well as uptake de novo synthesis of cholesterol could be an effective of oxidized-LDL, in human coronary artery endothelial method to reduce plasma cholesterol, and thereby poten-cells.The authors also demonstrate that oxidized-LDL tially reduce the incidence of atherosclerosis.The rate-causes a decrease in the phosphorylation state of PKB and limiting step in cholesterol synthesis is the reduction of that this effect was blocked by the two statins.The authors 3-hydroxy-3-methylglutaryl (HMG)-CoA to mevalonate, conclude that part of the cardioprotective effect of statins which is catalyzed by HMG-CoA reductase.This enzyme is due to their ability to decrease oxidized-LDL uptake by is an obvious target for inhibition in order to bring about a LOX-1 and that this effect is mediated by an increase in reduction in cholesterol synthesis and a corresponding drop PKB activity.This work is significant in that it demin plasma cholesterol.The first specific inhibitor of HMG-onstrates for the first time the ability of at least two statins CoA reductase to be discovered was a fungal metabolite to reverse the negative effects of oxidized LDL on LOX-1, named compactin [1,2], closely followed by mevinolin and because of the novel observation that these effects are [3,4].Synthetic derivatives of these compounds, along associated with modulation of PKB activity.with other naturally occurring compounds, have spawned a wide variety of clinically useful HMG-CoA reductase inhibitors collectively referred to as 'statins'.The ability of Pleiotropic effects of statins these inhibitors to effectively lower plasma cholesterol and reduce cardiovascular morbidity and mortality in patientsAlthough many studies have documented the ability of with and without cardiovascular disease has been docustatins to effectively lower plasma cholesterol levels [5-7], mented in numerous studies [5][6][7].However, beneficial evidence has steadily mounted for secondary beneficial effects of statins on vascular function beyond their ability effects of therapeutic doses of statins on cardiovascular to lower serum cholesterol have been noted, although disease that are apparently unrelated, or indirectly related, whether these effects were truly unrelated to their lipid to their lipid-lowering abilities [9,12].These are the solowering abilities has been unclear [8][9][10].These vascular called 'pleiotropic' effects, and include, but are not limited effects include improved endothelial function, decreased to, activities that show major clinical benefits such as coagulation, increased fibrinolysis, decreased inflammaendothelial function, inflammation, coagulation and plaque tion, and increased plaque stability, among other effects.vulnerability [8].Recent in vitro and in vivo evidence suggests that initial Endothelial function can be improved by increased release of nitric oxide (NO), which results in protective effects such as inhibition of platelet adhesion, inflamma-