Ezetimibe and Vascular Endothelial Function

Satoshi      Ikeda; Koji      Maemura

doi:10.2174/157016111793744797

Abstract

Hypercholesterolemia is a major risk factor for cardiovascular diseases that has been managed mostly with 3- hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors (statins) that suppress de novo cholesterol synthesis in the liver. Statins also have beneficial pleiotropic effects on the atherosclerotic process that are independent of their ability to lower lipid values. However, the levels of low-density lipoprotein cholesterol (LDL-C) in most hypercholesterolemic patients at high risk for cardiovascular disease do not reach the goals proposed by guidelines even when prescribed with statins. Ezetimibe is a new lipid-lowering agent that blocks the intestinal absorption of dietary and biliary cholesterol and reduces LDL-C levels, especially when combined with statins. However, its effect on cardiovascular events remains unknown. We reviewed the effects of ezetimibe on cardiovascular diseases, in particular, vascular endothelial function, which is initially impaired during the atherogenetic process and is an important predictor of cardiovascular events. The simultaneous inhibition of cholesterol synthesis by statin and of cholesterol absorption by ezetimibe might retard the atherogenetic process. These effects are considered to be mainly mediated by lipid lowering. However, further studies should elucidate the mechanism of the anti-atherosclerotic effects induced by ezetimibe; for instance, whether or not it directly affects atherogenesis independently from its lipid-lowering effects.

Keywords: Nitric oxide, C-reactive protein, oxidative stress, cardiovascular disease, atherosclerosis, hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors, low-density lipoprotein cholesterol, Ezetimibe, atherogenetic process, anti-atherosclerotic effects, dyslipidemia, NCEP, Adult Treatment Program, ATP-III, coronary heart disease, acylco-enzyme A, cholesterol acyltransferase, Nie-mann-Pick-like protein 1, nitric oxide (NO), prostacyclin, endothelium, –, derived hyperpo-larizing factor, endothelial NO synthase, eNOS, proatherogenic phenotype, endothe-lial progenitor cells, vascular endothelial growth factor (VEGF), tetrahy-drobiopterin (BH4), superoxide, acetylcholine, hypere-mia, plethysmography, estrogen replacement, atherogenesis, protein kinase C, nuclear factor kinase-kB, Justification for the Use of Statins in Prevention and Intervention Trial Evaluat-ing Rosuvastatin (JUPITER), high-sensitivity CRP (hs-CRP), HMG-CoA, isoprenoids, pyrophosphate, geranylgeranyl pyrophos-phate, GTP-binding proteins, Rho, Rac, Ras, geranylgeranylated, Caveolin, reactive oxygen species, NADPH, flow-mediated vasodilation, VCAM-1