Thromboxane a2 mediates iron-overload cardiomyopathy in mice through calcineurin-nuclear factor of activated t cells signaling pathway

Heng Lin, Hsiao Fen Li, Wei Shiung Lian, Hsi Hsien Chen, Yi Fan Lan, Pei Fang Lai, Ching Feng Cheng

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2586-2595
Number of pages10
JournalCirculation Journal
Volume77
Issue number10
DOIs
Publication statusPublished - 2013

Keywords

  • Calcineurin-nfat signaling
  • Cardiomyopathy
  • Iron overload
  • Thromboxane a2

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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