Ezetimibe and Vascular Inflammation

Toshiyuki      Ishibashi; Yasuchika      Takeishi

Abstract

Atherosclerosis is an inflammation-based complex vascular disorder which causes coronary artery disease, stroke and peripheral artery disease. Its pathophysiological process consists of endothelial dysfunction, monocyte adhesion to endothelial cells, lipid and inflammatory cell accumulation in the vascular wall, and migration and proliferation of smooth muscle cells. Both hyperlipidemia and inflammation are profoundly involved in each step. Cholesterol lowering by HMG-CoA reductase (statin) is beneficial for treating atherosclerotic coronary artery disease and stroke, together with reducing a surrogate-marker of inflammation, C-reactive protein (CRP). Another recently established cholesterol lowering tool using an intestinal cholesterol absorption inhibitor, ezetimibe, has been applied for clinical treatment of hypercholesterolemia for several reasons. First, hypercholesterolemia is associated with increased intestinal cholesterol absorption. Second, low cholesterol absorption prevents cardiovascular events. Third, cholesterol metabolism analysis provides evidence that the long-term use of statin increases cholesterol absorption. In terms of low-density lipoprotein cholesterol (LDL-C) and CRP reductions, the more powerful effect of ezetimibe has been seen when the agent is combined with statins. However, the effect of ezetimibe monotherapy on CRP reduction has not been well defined. This review provides information on recently described clinical trials of ezetimibe monotherapy, stain monotherapy, and combined therapy for LDL-C lowering and vascular inflammation.

Keywords: Atherosclerosis, cholesterol absorption, CRP, ezetimibe, inflammation, statin, vascular disorder, coronary artery disease, monocyte adhe-sion, hyperlipidemia, HMG-CoA reductase, diabetic mellitus, brachial artery flow-mediated, anti-thrombotic, anti-procoagulant effects, low-density lipoprotein, hypercholeste-loremia, Nieman-Pick-C1-Like1 (NPC1L1) protein, triglyceride, high-density lipo-protein cholesterol, GTPases, RhoA, Rac1, Cdc42, cytoskeleton organization, chemokines, thrombin, monocyte attractant protein-1, intercellular adhesion molecule-1, platelet endothelial cell adhesion molecule-1, produce platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), Angiotensin II, interferon, dendritic, NF-B activity, THP-1 cells, CD14 mRNA expression, apolipoprotein E (apoE), endothelial nitric oxide synthase, NADPH oxidase, angiotensin system (RAS), redox-sensitive signaling, fibrinolysis, tissue factor (TF), plasminogen activator, LOX-1, directional coronary atherec-tomy (DCA), interleukin-6 (IL-6), IL-1, IL-8 mRNA, MMP-9, secretory phospholipase A2, MMP-1, MMP-2, MMP-9, tumor necrosis factor- (TNF-)