Endoplasmic reticulum stress as a novel mechanism in amiodaroneinduced destructive thyroiditis

Angela Lombardi, William Barlow Inabnet, Randall Owen, Kaitlyn Ellen Farenholtz, Yaron Tomer

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Context: Amiodarone (AMIO) is one of the most effective antiarrhythmic drugs available; however, its use is limited by a serious side effect profile, including thyroiditis. The mechanisms underlying AMIO thyroid toxicity have been elusive; thus, identification of novel approaches in order to prevent thyroiditis is essential in patients treated with AMIO. Objective: Our aim was to evaluate whether AMIO treatment could induce endoplasmic reticulum (ER) stress in human thyroid cells and the possible implications of this effect in AMIO-induced destructive thyroiditis. Results: Here we report that AMIO, but not iodine, significantly induced the expression of ER stress markersincluding Igheavychain-binding protein (BiP), phosphoeukaryotic translation initiation factor 2α(eIF2α), CCAAT/enhancer-binding protein homologous protein (CHOP) and spliced X-box binding protein-1 (XBP-1) in human thyroid ML-1 cells and human primary thyrocytes. In both experimental systems AMIO down-regulated thyroglobulin (Tg) protein but had little effect on Tg mRNA levels, suggesting a mechanism involving Tg protein degradation. Indeed, pretreatment with the specific proteasome inhibitor MG132 reversed AMIO-induced down-regulation of Tg protein levels, confirming a proteasome-dependent degradation of Tg protein. Corroborating our findings, pretreatment of ML-1cellsandhumanprimarythyrocyteswiththechemicalchaperone4-phenylbutyric acidcompletely prevented the effect of AMIO on both ER stress induction and Tg down-regulation. Conclusions: We identified ER stress as a novel mechanism contributing to AMIO-induced destructive thyroiditis. Our data establish that AMIO-induced ER stress impairs Tg expression via proteasome activation, providing a valuable therapeutic avenue for the treatment of AMIO-induced destructive thyroiditis.

Original languageEnglish (US)
Pages (from-to)E1-E10
JournalJournal of Clinical Endocrinology and Metabolism
Volume100
Issue number1
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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