Ezetimibe ameliorates cardiovascular complications and hepatic steatosis in obese and type 2 diabetic db/db mice.
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.
Fukuda
Masaya
M
Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
Nakamura
Taishi
T
Kataoka
Keiichiro
K
Nako
Hisato
H
Tokutomi
Yoshiko
Y
Dong
Yi-Fei
YF
Yasuda
Osamu
O
Ogawa
Hisao
H
Kim-Mitsuyama
Shokei
S
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001384:Azetidines / Q000494:pharmacology*; D001794:Blood Pressure / Q000502:physiology; D001808:Blood Vessels / Q000187:drug effects / Q000502:physiology; D001823:Body Composition; D001835:Body Weight; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000235:genetics / Q000473:pathology; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000473:pathology; D000069438:Ezetimibe; D005234:Fatty Liver / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D005951:Glucose Tolerance Test; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007333:Insulin Resistance; D008099:Liver / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000201:enzymology; D019255:NADPH Oxidases / Q000378:metabolism; D009765:Obesity / Q000150:complications*; D013481:Superoxides / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D000924:Anticholesteremic Agents; D001384:Azetidines; D014280:Triglycerides; D013481:Superoxides; D002784:Cholesterol; D019255:NADPH Oxidases; D000069438:Ezetimibe