Loss of insulin receptor substrate-1 signaling induces the cardiovascular and proteo(fibrino)lytic system derangements typical of insulin resistance

In Brief 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. Type 2 diabetes and insulin resistance are associated with diastolic heart failure, impaired ventricular function, perimicrovascular fibrosis, and increased expression of PAI-1 in coronary arterial walls. To determine whether these regional manifestations can be induced by loss of IRS-1 mediated signaling we studied IRS-1 knockout (KO) mice at 20 weeks of age. Left ventricular mass/body weight increased; diastolic and systolic LV diameters increased; fractional shortening decreased; and coronary perimicrovascular fibrosis increased associated with increased immunoreactivity of PAI-1 in the tunica media. Thus, loss of IRS-1 signaling is sufficient to induce cardiac and proteo(fibrino)lytic system derangements typical of insulin resistance, and increased PAI-1 expression is not dependent on IRS-1 signaling.