Melatonin attenuated brain death tissue extract-induced cardiac damage by suppressing DAMP signaling

Pei Hsun Sung, Fan Yen Lee, Ling Chun Lin, Kuan Hung Chen, Hung Sheng Lin, Pei Lin Shao, Yi Chen Li, Yi Ling Chen, Kun Chen Lin, Chun Man Yuen, Hsueh Wen Chang, Mel S. Lee, Hon Kan Yip*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

17 Scopus citations

Abstract

We tested the hypothesis that melatonin prevents brain death (BD) tissue extract (BDEX)-induced cardiac damage by suppressing inflammatory damage-associated molecular pattern (DAMP) signaling in rats. Six hours after BD induction, levels of a DAMP component (HMGB1) and inflammatory markers (TLR-2, TLR-4, MYD88, IκB, NF-κB, IL-1β, IFN-γ, TNF-α and IL-6) were higher in brain tissue from BD animals than controls. Levels of HMGB1 and inflammatory markers were higher in BDEXtreated H9C2 cardiac myoblasts than in cells treated with healthy brain tissue extract. These increases were attenuated by melatonin but re-induced with luzindole (all P < 0.001). Additional male rats (n = 30) were divided into groups 1 (negative control), 2 (healthy brain tissue extract implanted in the left ventricular myocardium [LVM]), 3 (BDEX-LVM), 4 (BDEX-LVM + melatonin), and 5 (BDEX-LVM + melatonin + luzindole). Collagen deposition/fibrosis and LVM levels of MTR2, HMGB1, inflammatory markers, oxidative stress, apoptosis, mitochondrial damage and DNA damage were highest in group 3, lowest in groups 1 and 2, and higher in group 5 than in group 4. Heart function and LVM levels of MTR1 and anti-inflammatory, mitochondrial-integrity and anti-oxidative markers exhibited a pattern opposite that of the inflammatory markers in the five groups (all P < 0.0001). These results indicate melatonin inhibits BDEXinduced cardiac damage by suppressing the DAMP inflammatory axis.

Original languageEnglish
Pages (from-to)3531-3548
Number of pages18
JournalOncotarget
Volume9
Issue number3
DOIs
StatePublished - 2018

Bibliographical note

Publisher Copyright:
© Sung et al.

Keywords

  • Brain death
  • Damage-associated molecular patterns
  • Heart function
  • Inflammation
  • Remote organ

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