Abstract 839: Free Fatty Acids Inhibit Thrombomodulin Expression through Stress Signaling - An Implication for the Development of Prothrombotic State in Metabolic Syndrome
Metabolic syndrome displays a significant prothrombotic feature with increased risk for stroke, myocardial infarction and peripheral vascular diseases. However, the pathogenesis of the prothrombotic state in metabolic syndrome is not completely understood. One of the important features in metabolic syndrome is increased levels of free fatty acids (FFAs). In addition to being an important energy source, FFAs also act as signaling molecules regulating various cellular processes. A chronic elevation of FFAs, as seen in metabolic syndrome, may interfere with normal signaling and functions and contribute to the pathogenesis associated with metabolic syndrome. To determine whether FFAs’ have any effects on endothelial mediated thrombosis regulation, we examined the expression of prothrombotic factors von Willebrand factor (vWF), thromboxane A2 receptor (TXA2R), plasminogen activator inhibitor 1 (PAI-1) as well as anti-thrombotic factor thrombomodulin (TM) in FFA-treated human aortic endothelial cells. We observed that both palmitic acid and linoleic acid suppressed TM expression in a dose dependent manner with over 90% reduction at the dose of 0.5mM, whereas oleic acid had a minimal effect. Palmitic acid and linoleic acid inhibited TM expression at mRNA level. Additionally, the reduced TM expression led to decreased generation of activated protein C. To elucidate pathways for the TM suppression, we discovered that palmitic acid activated stress signaling JNK/AP-1 and inflammatory signaling IKK/NFkB pathways. Silencing JNK, AP-1 and NFkB with specific siRNAs reversed palmitic acid’s inhibitory effects on TM expression indicating that both pathways are involved in FFAs-induced TM down-regulation, probably by interfering with TM transcription. In summary, both palmitic acid and linoleic acid inhibit TM expression and protein C activation, which could account for prothrombotic status in patients with metabolic syndrome. Palmitic acid inhibits TM expression through JNK and NFkB pathways. Further studies along the direction may lead to the development of therapeutic strategies to attenuate this prothrombotic effect, hence reduce the cardiovascular complications in metabolic syndrome - an epidemic in 21st centaury (AHA-TX0565134Y).