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

Fingerprint

NFATC Transcription Factors
Thromboxane A2
Iron Overload
Calcineurin
Cardiomyopathies
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
Iron
Luciferases
Genes
Prostaglandins
Fibrosis
Prostaglandin H2 Receptors Thromboxane A2
Epoprostenol
Intercellular Adhesion Molecule-1
Cardiovascular System
Intraperitoneal Injections
Arachidonic Acid
Transgenic Mice
Peroxidase
Blood Vessels

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Thromboxane a2 mediates iron-overload cardiomyopathy in mice through calcineurin-nuclear factor of activated t cells signaling pathway. / Lin, Heng; Li, Hsiao Fen; Lian, Wei Shiung; Chen, Hsi Hsien; Lan, Yi Fan; Lai, Pei Fang; Cheng, Ching Feng.

In: Circulation Journal, Vol. 77, No. 10, 2013, p. 2586-2595.

Research output: Contribution to journalArticle

Lin, Heng ; Li, Hsiao Fen ; Lian, Wei Shiung ; Chen, Hsi Hsien ; Lan, Yi Fan ; Lai, Pei Fang ; Cheng, Ching Feng. / Thromboxane a2 mediates iron-overload cardiomyopathy in mice through calcineurin-nuclear factor of activated t cells signaling pathway. In: Circulation Journal. 2013 ; Vol. 77, No. 10. pp. 2586-2595.
@article{0c5cd222f48c435a8379bdbfd258c20c,
title = "Thromboxane a2 mediates iron-overload cardiomyopathy in mice through calcineurin-nuclear factor of activated t cells signaling pathway",
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.",
keywords = "Calcineurin-nfat signaling, Cardiomyopathy, Iron overload, Thromboxane a2",
author = "Heng Lin and Li, {Hsiao Fen} and Lian, {Wei Shiung} and Chen, {Hsi Hsien} and Lan, {Yi Fan} and Lai, {Pei Fang} and Cheng, {Ching Feng}",
year = "2013",
doi = "10.1253/circj.CJ-12-1516",
language = "English",
volume = "77",
pages = "2586--2595",
journal = "Circulation Journal",
issn = "1346-9843",
publisher = "Japanese Circulation Society",
number = "10",

}

TY - JOUR

T1 - Thromboxane a2 mediates iron-overload cardiomyopathy in mice through calcineurin-nuclear factor of activated t cells signaling pathway

AU - Lin, Heng

AU - Li, Hsiao Fen

AU - Lian, Wei Shiung

AU - Chen, Hsi Hsien

AU - Lan, Yi Fan

AU - Lai, Pei Fang

AU - Cheng, Ching Feng

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

KW - Calcineurin-nfat signaling

KW - Cardiomyopathy

KW - Iron overload

KW - Thromboxane a2

UR - http://www.scopus.com/inward/record.url?scp=84884617452&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84884617452&partnerID=8YFLogxK

U2 - 10.1253/circj.CJ-12-1516

DO - 10.1253/circj.CJ-12-1516

M3 - Article

C2 - 23856650

AN - SCOPUS:84884617452

VL - 77

SP - 2586

EP - 2595

JO - Circulation Journal

JF - Circulation Journal

SN - 1346-9843

IS - 10

ER -