TY - JOUR
T1 - Lipid-Lowering Therapy with Ezetimibe Decreases Spontaneous Atherothrombotic Occlusions in a Rabbit Model of Plaque Erosion
AU - Honda, Katsuya
AU - Matoba, Tetsuya
AU - Antoku, Yoshibumi
AU - Koga, Junichiro
AU - Ichi, Ikuyo
AU - Nakano, Kaku
AU - Tsutsui, Hiroyuki
AU - Egashira, Kensuke
N1 - Funding Information:
This study was financially supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture, Tokyo, Japan (15K19384 and 17K16011 to J. Koga, 17K09590 to T. Matoba, 25293185 to K. Egashira), the Ministry of Health Labor and Welfare, Tokyo, Japan (Health Science Research Grants, Research on Translational Research, Intractable Diseases, and Nanomedicine to K. Egashira), intractable diseases overcome research project from the Japan Agency for Medical Research and Development (to K. Egashira), and Bayer Yakuhin Ltd (to K. Egashira). Bayer Yakuhin Ltd had no role in the design, execution, analysis, or interpretation of this study.
Publisher Copyright:
© 2018 American Heart Association, Inc.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - Objective - Plaque erosion is increasing its importance as one of the mechanisms of acute coronary syndromes in this statin era. However, the clinical efficacy of currently used lipid-lowering agents in the prevention of thrombotic complications associated with plaque erosion has not been clarified. Therefore, we examined the therapeutic effects of ezetimibe or rosuvastatin monotherapy on spontaneous atherothrombotic occlusion. Approach and Results - Femoral arteries of Japanese white rabbits, fed a high-cholesterol diet, were injured by balloon catheter, and then angiotensin II was continuously administrated. In 94% of these arteries, spontaneous thrombotic occlusions were observed after 5 weeks (median) of balloon injury. Histochemical analyses indicated that the injured arteries had similar pathological features to human plaque erosions; (1) spontaneous thrombotic occlusion, (2) lack of endothelial cells, and (3) tissue factor expression in vascular smooth muscle cells. Ezetimibe (1.0 mg/kg per day), but not rosuvastatin (0.6 mg/kg per day), significantly decreased thrombotic occlusion of arteries accompanied with accelerated re-endothelialization and the decreases of serum oxysterols despite the comparable on-treatment serum cholesterol levels. The 7-ketocholesterol inhibited the migration of human umbilical vein endothelial cells. Both 7-ketocholesterol and 27-hydroxycholesterol increased tissue factor expression in cultured rat vascular smooth muscle cells. Tissue factor expression was also induced by serum from vehicle- or rosuvastatin-treated rabbits, but the induction was attenuated with serum from ezetimibe-treated rabbits. Conclusions - We have established a novel rabbit model of spontaneous atherothromobotic occlusion without plaque rupture that is feasible to test the therapeutic effects of various pharmacotherapies. Ezetimibe may decrease atherothrombotic complications after superficial plaque erosion by reducing serum oxysterols.
AB - Objective - Plaque erosion is increasing its importance as one of the mechanisms of acute coronary syndromes in this statin era. However, the clinical efficacy of currently used lipid-lowering agents in the prevention of thrombotic complications associated with plaque erosion has not been clarified. Therefore, we examined the therapeutic effects of ezetimibe or rosuvastatin monotherapy on spontaneous atherothrombotic occlusion. Approach and Results - Femoral arteries of Japanese white rabbits, fed a high-cholesterol diet, were injured by balloon catheter, and then angiotensin II was continuously administrated. In 94% of these arteries, spontaneous thrombotic occlusions were observed after 5 weeks (median) of balloon injury. Histochemical analyses indicated that the injured arteries had similar pathological features to human plaque erosions; (1) spontaneous thrombotic occlusion, (2) lack of endothelial cells, and (3) tissue factor expression in vascular smooth muscle cells. Ezetimibe (1.0 mg/kg per day), but not rosuvastatin (0.6 mg/kg per day), significantly decreased thrombotic occlusion of arteries accompanied with accelerated re-endothelialization and the decreases of serum oxysterols despite the comparable on-treatment serum cholesterol levels. The 7-ketocholesterol inhibited the migration of human umbilical vein endothelial cells. Both 7-ketocholesterol and 27-hydroxycholesterol increased tissue factor expression in cultured rat vascular smooth muscle cells. Tissue factor expression was also induced by serum from vehicle- or rosuvastatin-treated rabbits, but the induction was attenuated with serum from ezetimibe-treated rabbits. Conclusions - We have established a novel rabbit model of spontaneous atherothromobotic occlusion without plaque rupture that is feasible to test the therapeutic effects of various pharmacotherapies. Ezetimibe may decrease atherothrombotic complications after superficial plaque erosion by reducing serum oxysterols.
UR - http://www.scopus.com/inward/record.url?scp=85044354654&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044354654&partnerID=8YFLogxK
U2 - 10.1161/ATVBAHA.117.310244
DO - 10.1161/ATVBAHA.117.310244
M3 - Article
C2 - 29449331
AN - SCOPUS:85044354654
SN - 1079-5642
VL - 38
SP - 757
EP - 771
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 4
ER -