Abstract 1661: Insulin Stimulates and Inhibits the Expression of Anticoagulant Thrombomodulin through Different Pathways: An Implication for the Development of Prothrombotic State in Metabolic Syndrome

Metabolic syndrome displays a significant prothrombotic tendency which renders the patients highly susceptible to stroke, myocardial infarction and peripheral vascular occlusive diseases. However, the pathogenesis of the prothrombotic state in metabolic syndrome is not completely understood. One major feature in metabolic syndrome is a global insulin resistance with subsequent hyperinsulinemia. We therefore examined insulin’s effects on anticoagulant thrombomodulin-protein C system. We observed that insulin had biphasic effects on thrombomodulin (TM) expression in human aortic endothelial cells. Insulin stimulated TM expression at lower dose (0.05–1nM) in a dose dependent manor. However, at higher dose range (5–100nM), insulin exhibited a dose dependent inhibition of TM expression with over 90% reduction at dose of 100nM. We further elucidated signaling pathways responsible for insulin-regulated TM expression. Insulin activated Akt and Erk pathways. Silencing Akt with specific siRNAs abolished insulin’s stimulatory effect on TM expression indicating that insulin increases TM expression via Akt pathway. Suppressing Erk with siRNA reversed the inhibition of TM expression induced by high concentration of insulin, suggesting that insulin decreases TM expression through Erk pathway. Interestingly, palmitic acid significantly amplified insulin’s inhibitory effect on TM expression. Palmitic acid selectively inhibited insulin stimulated Akt pathway and reduced TM expression, while had minimal effects on insulin-activated Erk pathway. In summary, low dose of insulin stimulates TM expression through Akt pathway, while high dose of insulin inhibits TM expression via Erk pathway. Palmitic acid modulates insulin’s effects on TM expression by selectively inhibiting Akt pathway; the resulting decrease in TM expression may be a factor in the prothrombotic state in metabolic syndrome. Further studies on the relationship between free fatty acids, insulin, and TM may lead to the development of therapeutic strategies to attenuate the prothrombotic tendency and reduce the cardiovascular complications in metabolic syndrome. This research has received full or partial funding support from the American Heart Association, AHA National Center.