title: Loss of insulin receptor substrate-1 signaling induces the cardiovascular and proteo(fibrino)lytic system derangements typical of insulin resistance.
abstract: BACKGROUND
  Type 2 diabetes and insulin resistance have been associated with several cardiac features including diastolic heart failure, impaired ventricular function, perimicrovascular fibrosis and increased expression of plasminogen activator inhibitor type-1 (PAI-1) in coronary arterial walls. Insulin receptor substrate-1 (IRS-1) is one mediator of insulin signaling. This study was performed to determine whether induction of cardiac manifestations typical of insulin resistance and increased PAI-1 expression occur developmentally or post-developmentally as a result of loss of IRS-1-mediated signaling.
  
  
  METHODS
  IRS-1 knockout mice were studied at 20 weeks of age.
  
  
  RESULTS
  Compared with control mice, the left ventricular (LV) and cardiac mass to body weight ratios were increased. Diastolic and systolic LV diameters and decreased fractional shortening were indicative of LV dilatation and dysfunction. Coronary perimicrovascular fibrosis, an increased coronary arterial wall to lumen ratio, increased immunoreactivity of PAI-1 in the tunica media and increased PAI-1 mRNA expression were present consistent with constrained mural proteo(fibrino)lysis. These cardiac manifestations were similar to those we and others have observed previously in insulin-resistant mice without impaired IRS-1-mediated signaling.
  
  
  CONCLUSIONS
  Loss of IRS-1 signaling is sufficient to induce cardiac manifestations typical of insulin resistance including increased coronary arterial mural PAI-1 expression. Furthermore, increased PAI-1 expression is not dependent on IRS-1 signaling.
authors.affiliation: Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Furumoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fujii
authors.forename: Hisao
authors.initials: H
authors.lastname: Onozuka
authors.forename: A K M
authors.initials: AK
authors.lastname: Tarikuz Zaman
authors.forename: Daisuke
authors.initials: D
authors.lastname: Goto
authors.forename: Taeko
authors.initials: T
authors.lastname: Sugawara
authors.forename: Taisei
authors.initials: T
authors.lastname: Mikami
authors.forename: Satoshi
authors.initials: S
authors.lastname: Watanabe
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Abe
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Akira
authors.initials: A
authors.lastname: Kitabatake
authors.forename: Burton E
authors.initials: BE
authors.lastname: Sobel
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015152:Blotting, Northern; D003331:Coronary Vessels / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004452:Echocardiography; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007124:Immunoenzyme Techniques; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D010750:Phosphoproteins / Q000172:deficiency* / Q000235:genetics; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D015415:Biomarkers; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D017395:Plasminogen Activator Inhibitor 1; D012313:RNA