Loss of insulin receptor substrate-1 signaling induces the cardiovascular and proteo(fibrino)lytic system derangements typical of insulin resistance.
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.
Furumoto
Tomoo
T
Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Fujii
Satoshi
S
Onozuka
Hisao
H
Tarikuz Zaman
A K M
AK
Goto
Daisuke
D
Sugawara
Taeko
T
Mikami
Taisei
T
Watanabe
Satoshi
S
Abe
Kazuhiro
K
Terauchi
Yasuo
Y
Kadowaki
Takashi
T
Kitabatake
Akira
A
Sobel
Burton E
BE
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*
D015415:Biomarkers; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D017395:Plasminogen Activator Inhibitor 1; D012313:RNA