| Ezetimibe ameliorates cardiovascular complications and hepatic steatosis in obese and type 2 diabetic db/db mice. | |
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MedLine Citation:
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PMID: 20651026 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Type 2 diabetes plays a major role in the development of cardiovascular diseases. The present study was undertaken to investigate the effect of ezetimibe, a potent cholesterol absorption inhibitor, on cardiovascular injury of obese and type 2 diabetic db/db mice. Diabetic db/db mice fed a Western diet were given ezetimibe for 9 weeks, and the effects on cardiovascular injury and hepatic steatosis were examined. Ezetimibe treatment of db/db mice significantly improved vascular endothelial function, which was associated with the restoration of the decreased phospho-Akt and phospho-endothelial nitric-oxide synthase (eNOS). Moreover, ezetimibe also reduced vascular superoxide levels in db/db mice, accompanied by the attenuation of NADPH oxidase subunit gp91(phox) and Nox4 and the prevention of down-regulation of Cu/Zn-superoxide dismutase (SOD) and extracellular SOD. Thus, the improvement of vascular endothelial function by ezetimibe in diabetic mice seems to be attributed to the improvement of eNOS function and the attenuation of oxidative stress. Ezetimibe treatment also significantly attenuated cardiac interstitial fibrosis and coronary arterial thickening of diabetic mice and ameliorated cardiac macrophage infiltration. This improvement of cardiac injury was also related to the attenuation of NADPH oxidase-mediated oxidative stress. Furthermore, ezetimibe significantly prevented hepatic steatosis, inflammation, and oxidative stress in diabetic mice. Our work provides the first evidence that ezetimibe prevented cardiovascular injury and hepatic steatosis in diabetic mice. These beneficial effects were attributed to the attenuation of oxidative stress and inflammation and the improvement of eNOS function. Therefore, we propose that ezetimibe may be a promising therapeutic drug for obese and type 2 diabetes. |
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Authors:
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Masaya Fukuda; Taishi Nakamura; Keiichiro Kataoka; Hisato Nako; Yoshiko Tokutomi; Yi-Fei Dong; Osamu Yasuda; Hisao Ogawa; Shokei Kim-Mitsuyama |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't Date: 2010-07-22 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 335 ISSN: 1521-0103 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-09-21 Completed Date: 2010-10-21 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 70-5 Citation Subset: IM |
Affiliation:
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Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anticholesteremic Agents / pharmacology* Azetidines / pharmacology* Blood Pressure / physiology Blood Vessels / drug effects, physiology Body Composition Body Weight Cardiovascular Diseases / drug therapy*, etiology*, pathology Cholesterol / metabolism Diabetes Mellitus, Type 2 / complications*, genetics, pathology Diabetic Angiopathies / drug therapy*, pathology Fatty Liver / drug therapy*, etiology, pathology Glucose Tolerance Test Immunohistochemistry Insulin Resistance Liver / chemistry, enzymology, metabolism Male Mice Mice, Inbred C57BL Myocardium / enzymology NADPH Oxidase / metabolism Obesity / complications* Superoxides / metabolism Triglycerides / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Anticholesteremic Agents; 0/Azetidines; 0/Triglycerides; 11062-77-4/Superoxides; 163222-33-1/ezetimibe; 57-88-5/Cholesterol; EC 1.6.3.1/NADPH Oxidase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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