Ezetimibe Improves Endothelial Function and Inhibits Rho-Kinase Activity Associated With Inhibition of Cholesterol Absorption in Humans

• Published in: Circulation Journal Vol. 76; no. 8; pp. 2023 - 2030
• Main Authors: Nochioka, Kotaro, Tanaka, Shin-ichi, Miura, Masanobu, Zhulanqiqige, Do.e, Fukumoto, Yoshihiro, Shiba, Nobuyuki, Shimokawa, Hiroaki
• Format: Journal Article
• Language: English
• Published: Japan The Japanese Circulation Society 2012
• Subjects: Adult; Anticholesteremic Agents - administration & dosage; Azetidines - administration & dosage; Cholestanol - blood; Cholesterol - blood; Cholesterol - metabolism; Cross-Sectional Studies; Endothelium, Vascular - metabolism; Ezetimibe; Female; Flow-mediated dilatation; Gene Expression Regulation, Enzymologic - drug effects; Humans; Intestinal Absorption - drug effects; LDL cholesterol; Leukocytes - metabolism; Male; Pravastatin - administration & dosage; rho-Associated Kinases - antagonists & inhibitors; rho-Associated Kinases - metabolism; Rho-kinase; Up-Regulation - drug effects
• ISSN: 1346-9843; 1347-4820
• DOI: 10.1253/circj.CJ-12-0331

Background: Ezetimibe is an inhibitor of cholesterol absorption in the intestine. We examined whether ezetimibe improves endothelial function, and if so, what mechanisms are involved. Methods and Results: Nineteen healthy subjects (male/female 14/5; mean age, 31±3 [SD] years-old) were randomized to receive ezetimibe (10mg/day) or pravastatin (10mg/day) for 4 weeks in a cross-over manner with a 4-week washout interval. Lipid profiles, flow-mediated dilatation (FMD) and Rho-kinase activity of circulating leukocytes (the extent of phosphorylation of myosin binding subunit, a Rho-kinase substrate) were examined. We also evaluated remnant-like particle cholesterol (RLP-C) known as an up-regulator of Rho-kinase and cholesterol absorption status by measuring cholestanol and campesterol/lathosterol ratio (CLR) (both absorption markers). Although ezetimibe and pravastatin equally reduced low-density lipoprotein cholesterol (E: -25% vs. P: -21%), the CLR was reduced by ezetimibe but was rather increased by pravastatin (E: -41% vs. P: +37%; P<0.01). Reduction in RLP-C by ezetimibe was greater compared with pravastatin (E: -33% vs. P: -14%; P<0.05). Importantly, ezetimibe significantly improved FMD (26%, P<0.05) and reduced Rho-kinase activity (-21%, P<0.05), whereas pravastatin had no such effects. A significant correlation was noted between the reduction in cholestanol and the improvement in FMD (P<0.05). Conclusions: These results indicate that ezetimibe improves endothelial function and inhibits Rho-kinase activity associated with the inhibition of cholesterol absorption, suggesting novel anti-atherogenic effects of the agent in humans.  (Circ J 2012; 76: 2023–2030)