title: Thromboxane A2 mediates iron-overload cardiomyopathy in mice through calcineurin-nuclear factor of activated T cells signaling pathway.
abstract: 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.
  
  
  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.
authors.affiliation: Institute of Physiology, College of Medicine, Taipei Medical University.
authors.forename: Heng
authors.initials: H
authors.lastname: Lin
authors.forename: Hsiao-Fen
authors.initials: HF
authors.lastname: Li
authors.forename: Wei-Shiung
authors.initials: WS
authors.lastname: Lian
authors.forename: Hsi-Hsien
authors.initials: HH
authors.lastname: Chen
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Lan
authors.forename: Pei-Fang
authors.initials: PF
authors.lastname: Lai
authors.forename: Ching-Feng
authors.initials: CF
authors.lastname: Cheng
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D009202:Cardiomyopathies / Q000097:blood* / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D016207:Cytokines / Q000097:blood / Q000235:genetics; D000069285:Infliximab; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood / Q000235:genetics; D019190:Iron Overload / Q000097:blood* / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D013928:Thromboxane A2 / Q000097:blood* / Q000235:genetics; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D016207:Cytokines; D050778:NFATC Transcription Factors; D014662:Vasoconstrictor Agents; D018799:Intercellular Adhesion Molecule-1; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000069285:Infliximab