Free fatty acids inhibit TM-EPCR expression through JNK pathway: an implication for the development of the prothrombotic state in metabolic syndrome.
Metabolic syndrome is associated with significant hypercoagulable prothrombotic tendency; however, the mechanism for the prothrombotic state is not completely understood. We hypothesize that higher circulating plasma free fatty acids (FFAs) in metabolic syndrome inhibit the endothelial thrombomodulin (TM)-endothelial protein C receptor (EPCR) pathway, thereby promoting thrombus formation. Human umbilical vein endothelial cells were cultured in media supplemented with various doses of palmitic acid (PA), in the presence or absence of JNK inhibitor, and the expression of TM and EPCR was measured by western blot. The thrombotic state of high fat fed C57BL/6J mice was examined by tail bleeding time and deep venous thrombosis (DVT) model. As a result, PA inhibited the expression of TM and EPCR in endothelial cells, and this effect was blunted by inhibiting JNK signaling. High fat diet fed mice had higher level of circulating FFAs and exhibited prothrombotic state, evidenced by increased tail bleeding time and enlarged thrombotic size in DVT model, compared to the control diet fed mice. Hence, FFAs inhibit TM-EPCR-Protein C system in endothelial cells through activating JNK signaling, which may be a mechanism for the prothrombotic state in metabolic syndrome.
Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People's Republic of China.
Wanmu
W
Xie
Zhenguo
Z
Zhai
Yuanhua
Y
Yang
Tuguang
T
Kuang
Chen
C
Wang
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis*; D001760:Bleeding Time; D002478:Cells, Cultured; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D000074283:Endothelial Protein C Receptor; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D011956:Receptors, Cell Surface / Q000096:biosynthesis*; D015398:Signal Transduction; D018180:Thrombomodulin / Q000096:biosynthesis*; D020246:Venous Thrombosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology
D015703:Antigens, CD; D004041:Dietary Fats; D000074283:Endothelial Protein C Receptor; D005230:Fatty Acids, Nonesterified; C478370:PROCR protein, human; D011956:Receptors, Cell Surface; D018180:Thrombomodulin; D048670:MAP Kinase Kinase 4