Abstract 4942: Identification of Insulin Receptor Substrate Family Proteins Mediating PAI-1 Production in Cardiac and Adipose Tissues From IRS-1 Null Mice
Obesity is associated with dysfunctional insulin receptor substrate (IRS)-1 pathway and compensatory hyperinsulinemia. Insulin can stimulate production of plasminogen activator inhibitor (PAI)-1, the physiologic inhibitor of fibrinolysis, in adipocytes. Because hypofibrinolysis by PAI-1 confers cardiovascular risk, the role of IRS-1-mediated signaling in PAI-1 expression was elucidated in IRS-1 knockout (KO) mice. PAI-1 mRNA was increased by 10-fold in adipose tissue from IRS-1 KO (P<0.001). Abdominal adipocyes isolated from IRS-1 KO released 11-fold more PAI-1 to the conditioned media (P<0.001), indicating increased PAI-1 production in IRS-1 KO. IRS-2 was barely detectable in abdominal adipose tissue of IRS-1 KO. In contrast, IRS-3 was increased by 60% in IRS-1 KO, suggesting that IRS-3-mediated pathway was compensating for the lack of IRS-1 in adipose tissue. PAI-1 mRNA was increased in IRS-1 heart and perivascular fibrosis was persistently augmented, suggesting that PAI-1 can contribute to coronary arterial remodeling. In IRS-1 KO, cardiac expressions of IRS-2 and p85, a substrate of IRS-2, were increased by 2.7- and 2.4-fold over control and active JNK1 was increased by 1.36-fold and active JNK2 was increased by 2.18-fold, suggesting the presence of compensatory IRS-2-mediated pathway. Thus, impaired IRS-1 mediated signaling can be compensated by diverse alternative pathways in IRS-1 KO. These alternative pathways may contribute to persistent PAI-1 expression and hypofibrinlysis in the setting of hyperinsulinemia in obesity.