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Thaliporphine ameliorates cardiac depression in endotoxemic rats through attenuating TLR4 signaling in the downstream of TAK-1 phosphorylation and NF-κB signaling

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Abstract

Thaliporphine was found to ameliorate endotoxin-induced circulatory failure and mortality in rodents. The aims of the present study were to assess whether thaliporphine could improve cardiac function in endotoxemic rats and to investigate the underlying mechanisms. Cardiac function was evaluated by pressure–volume loop analysis in pentobarbital-anesthetized rats 24 h after intravenous injection of lipopolysaccharide (LPS) (4 mg/kg) with or without thaliporphine (1 mg/kg, iv). The intracellular Ca2+ transients, nitric oxide (NO), and reactive oxygen species (ROS) in enzymatically isolated ventricular cells were measured by fluorescent indicators. Western blotting was used to analyze the change of protein expression in response to LPS with or without thaliporphine in rat ventricle, H9C2 and Raw264.7 cells. Cardiac depression was found to coincide with the decreased intracellular Ca2+ transients and the increased expression of nitrotyrosine on SERCA2 in rat ventricles after 24-h endotoxemia. Thaliporphine decreased intracellular NO and ROS level in ventricular cells and the nitrosylation of SERCA2, which resulted in recovering the functional properties of intracellular Ca2+ handling and cardiac contraction. In H9C2 cells, LPS-induced nuclear translocation of nuclear factor kappa B (NF-κB) could be attenuated by thaliporphine. In Raw264.7 cells, thaliporphine attenuated LPS-induced TAK-1 phosphorylation and IκBα degradation in association with the inhibition of inducible nitric oxide synthase (iNOS) and tumor necrosis factor alpha (TNF-α) expression and the production of NO and ROS. In conclusion, thaliporphine ameliorates LPS-induced cardiac depression through attenuating TLR4 signaling in the downstream of TAK-1 phosphorylation and NF-κB signaling in both cardiomyocytes and macrophage to prevent cardiac SERCA2 from nitrosylation by peroxynitrite via decreasing iNOS and TNF-α expression.

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Abbreviations

LPS:

Lipopolysaccharide

TLR-4:

Toll-like receptor 4

iNOS:

Inducible nitric oxide synthase

COX-2:

Cyclooxygenase 2

TNF-α:

Tumor necrosis factor alpha

NCX:

Sodium calcium exchanger

SERCA-2:

Sarcoplasmic reticulum Ca2+-ATPase

PLB:

Phospholamban

CXN43:

Connexin 43

NO:

Nitric oxide

ROS:

Reactive oxygen species

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Acknowledgements

This work was supported by grants from the National Science Council (NSC 95-2323-B-002-013), Taiwan.

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Authors and Affiliations

  1. Institute of Pharmacology, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Rd, Taipei, 100, Taiwan

    Wen-Pin Chen, Hsiao-Jung Tzeng, Hui-Chun Ku, Yi-Jin Ho & Ming-Jai Su

  2. School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan

    Shoei-Sheng Lee

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  1. Wen-Pin Chen
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Correspondence to Ming-Jai Su.

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Chen, WP., Tzeng, HJ., Ku, HC. et al. Thaliporphine ameliorates cardiac depression in endotoxemic rats through attenuating TLR4 signaling in the downstream of TAK-1 phosphorylation and NF-κB signaling. Naunyn-Schmied Arch Pharmacol 382, 441–453 (2010). https://doi.org/10.1007/s00210-010-0562-1

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