Increased insulin, triglycerides, reactive oxygen species, and cardiac fibrosis in mice with a mutation in the helicase domain of the Werner syndrome gene homologue

被引:53
作者
Massip, L
Garand, C
Turaga, RVN
Deschênes, F
Thorin, E
Lebel, M
机构
[1] Univ Laval, Ctr Rech Cancerol, Hop Hotel Dieu, CHUQ, Quebec City, PQ G1R 2J6, Canada
[2] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada
基金
加拿大健康研究院;
关键词
Werner syndrome; mouse DNA helicase; cardiovascular disease; oxidative stress; hyperinsulinemia; hyperglycemia; hypertriglyceridemia; hypercholesterolemia;
D O I
10.1016/j.exger.2005.10.011
中图分类号
R592 [老年病学]; C [社会科学总论];
学科分类号
03 ; 0303 ; 100203 ;
摘要
Werner Syndrome (WS) is a rare disorder characterized by the premature onset of a number of age-related diseases. The gene responsible for WS encodes a DNA helicase/exonuclease protein. Previously, we generated a mouse model lacking part of the helicase domain of the murine Wrn homologue. Mutant Wm(Delta hel/Delta hel) mice developed severe cardiac interstitial fibrosis in addition to tumors. Further analyses of these mice on the pure C57B1/6 genetic background revealed abnormal increases in visceral fat deposition, fasting blood triglyceride and cholesterol levels followed by insulin resistance and high blood glucose levels. These phenotypes were more severe in mutant females than mutant males. In addition, adult mice had clear hemodynamic signs of aortic stenosis. All these symptoms appeared before the onset of cardiomyopathy and are known to cause heart failure. Interestingly, Wrn(Delta hel/Delta hel) adult mice (but not juveniles) showed higher levels of serum and cardiac tissue reactive oxygen species followed in time by an increase in cardiac oxidative DNA damage, all this prior to cardiac fibrosis. (c) 2005 Elsevier Inc. All rights reserved.
引用
收藏
页码:157 / 168
页数:12
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