Thromboxane A2 Mediates Iron-Overload Cardiomyopathy in Mice Through Calcineurin-Nuclear Factor of Activated T Cells Signaling Pathway

スポンサーリンク

概要

• 論文の詳細を見る

• 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.

著者

• Lian Wei-shiung

  Institute Of Biomedical Sciences Academia Sinica

• Cheng Ching-Feng

  Department of Medical Research, Tzu Chi General Hospital and Department of Pediatrics, Tzu Chi University

• Li Hsiao-Fen

  Institute of Biomedical Sciences, Academia Sinica

• Lin Heng

  Institute of Physiology, College of Medicine, Taipei Medical University

• Chen Hsi-Hsien

  Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University

• Lan Yi-Fan

  Institute of Pharmacology and Toxicology, Tzu Chi University

• Lai Pei-Fang

  Institute of Pharmacology and Toxicology, Tzu Chi University

• Lian Wei-Shiung

  Institute of Biomedical Sciences, Academia Sinica

関連論文

• PE-036 Abnormal cardiac autonomic regulation and susceptibility to cardiac ischemia in mice lack of ASIC3(Autonomic nervous system(03)(H),Poster Session(English),The 72nd Annual Scientific Meeting of the Japanese Circulation Society)
• Acid-Sensing Ion Channel 3, But Not Capsaicin Receptor TRPV1, Plays a Protective Role in Isoproterenol-Induced Myocardial Ischemia in Mice
• Thromboxane A2 Mediates Iron-Overload Cardiomyopathy in Mice Through Calcineurin-Nuclear Factor of Activated T Cells Signaling Pathway

スポンサーリンク