Increased insulin, triglycerides, reactive oxygen species, and cardiac fibrosis in mice with a mutation in the helicase domain of the Werner syndrome gene homologue.
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 WrnDeltahel/Deltahel mice developed severe cardiac interstitial fibrosis in addition to tumors. Further analyses of these mice on the pure C57Bl/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, WrnDeltahel/Deltahel 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.
Massip
Laurent
L
Centre de Recherche en Cancérologie de l'Université Laval, Hôpital Hôtel-Dieu de Québec, CHUQ, 9 McMahon St, Québec, Qué., Canada G1R 2J6.
Garand
Chantal
C
Turaga
Ramachander V N
RV
Deschênes
François
F
Thorin
Eric
E
Lebel
Michel
M
D000818:Animals; D004265:DNA Helicases / Q000235:genetics*; D005355:Fibrosis; D017353:Gene Deletion; D007328:Insulin / Q000097:blood*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009154:Mutation; D009206:Myocardium / Q000473:pathology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D017382:Reactive Oxygen Species / Q000097:blood*; D053484:RecQ Helicases; D017385:Sequence Homology; D014280:Triglycerides / Q000097:blood*; D000071657:Werner Syndrome Helicase
D007328:Insulin; D017382:Reactive Oxygen Species; D014280:Triglycerides; D004265:DNA Helicases; D053484:RecQ Helicases; D000071657:Werner Syndrome Helicase; C499253:Wrn protein, mouse