Thromboxane A<sub>2</sub> Mediates Iron-Overload Cardiomyopathy in Mice Through Calcineurin-Nuclear Factor of Activated T Cells Signaling Pathway

DOI Web Site PubMed 参考文献42件
  • Lin Heng
    Institute of Physiology, College of Medicine, Taipei Medical University
  • Li Hsiao-Fen
    Institute of Biomedical Sciences, Academia Sinica
  • Lian Wei-Shiung
    Institute of Biomedical Sciences, Academia Sinica
  • Chen Hsi-Hsien
    Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University Department of Internal Medicine, Taipei Medical University Hospital
  • Lan Yi-Fan
    Institute of Pharmacology and Toxicology, Tzu Chi University
  • Lai Pei-Fang
    Institute of Pharmacology and Toxicology, Tzu Chi University
  • Cheng Ching-Feng
    Department of Medical Research, Tzu Chi General Hospital and Department of Pediatrics, Tzu Chi University Institute of Biomedical Sciences, Academia Sinica

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Background: Recent studies demonstrated that iron overload could enhance the production of arachidonic acid and prostanoid, suggesting a causal connection between these signals and iron-overload cardiomyopathy. However, information regarding the downstream signaling is limited. Because thromboxane A2 (TXA2) and prostacyclin are the 2 major prostanoids in the cardiovascular system, and TXA2 plays a major role in vascular atherosclerosis and has pro-inflammatory characteristics, we intended to elucidate the role of TXA2 in iron-overload cardiomyopathy. Methods and Results: A 4-week iron loading protocol was instituted for both TXAS gene-deleted (TXAS−/−) mice and wild-type (WT) mice, with less severe cardiac fibrosis and preserved normal left ventricular contraction in the TXAS−/− mice. Inflammatory profiles, including MCP-1, TNF-α, IL-6, ICAM-1, and myeloperoxidase activity were also lower in the TXAS−/− as compared with WT littermates. TXAS supplement to the iron-injured TXAS−/− mice re-aggravated cardiac inflammation. Using a TXA2 analog, U46619, for NFAT reporter luciferase activity on cardiomyoctes, and intraperitonal injection of U46619 into nuclear factor of activated T cells (NFAT)-luciferase transgenic mice demonstrated that U46619 increase NFAT expression, and this expression, as well as TNF-α expression, can be blocked by TXA2 receptor antagonist (SQ29548), NFAT-SiRNA, calcineurin inhibitor, or calcium chelator. Finally, intraperitoneal injection of the TNF-α antibody, infliximab, into iron-injured mice decreased TXAS expression and attenuated cardiac fibrosis. Conclusions: TXA2 mediates iron-overload cardiomyopathy through the TNF-α-associated calcineurin-NFAT signaling pathway.  (Circ J 2013; 77: 2586–2595)<br>

収録刊行物

  • Circulation Journal

    Circulation Journal 77 (10), 2586-2595, 2013

    一般社団法人 日本循環器学会

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