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Free fatty acids inhibit TM–EPCR expression through JNK pathway: an implication for the development of the prothrombotic state in metabolic syndrome

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Abstract

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.

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Authors and Affiliations

  1. Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China

    Wanmu Xie, Zhenguo Zhai, Yuanhua Yang & Tuguang Kuang

  2. Beijing Key Laboratory of Respiratory and Pulmonary Circulation, Beijing Institute of Respiratory Medicine, 8 Gongren Tiyuchang South Road, Beijing, 100020, People’s Republic of China

    Wanmu Xie, Zhenguo Zhai, Yuanhua Yang, Tuguang Kuang & Chen Wang

  3. Beijing Hospital of Ministry of Health, Beijing, People’s Republic of China

    Chen Wang

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  1. Wanmu Xie
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  2. Zhenguo Zhai
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  3. Yuanhua Yang
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  4. Tuguang Kuang
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  5. Chen Wang
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Correspondence to Chen Wang.

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Xie, W., Zhai, Z., Yang, Y. et al. Free fatty acids inhibit TM–EPCR expression through JNK pathway: an implication for the development of the prothrombotic state in metabolic syndrome. J Thromb Thrombolysis 34, 468–474 (2012). https://doi.org/10.1007/s11239-012-0793-8

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