期刊
EXPERIMENTAL GERONTOLOGY
卷 41, 期 2, 页码 157-168出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.exger.2005.10.011
关键词
Werner syndrome; mouse DNA helicase; cardiovascular disease; oxidative stress; hyperinsulinemia; hyperglycemia; hypertriglyceridemia; hypercholesterolemia
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.
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