Syringaresinol protects against hypoxia/reoxygenation-induced cardiomyocytes injury and death by destabilization of HIF-1a in a FOXO3-dependent mechanism

Siyoung Cho, Miook Cho, Juewon Kim, Matt Kaeberlein, Sang Jun Lee, Yousin Suh

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Hypoxia-inducible factor 1 (HIF-1) is a master regulator of hypoxic response and has been a prime therapeutic target for ischemia/reperfusion (I/R)-derived myocardial dysfunction and tissue damage. There is also increasing evidence that HIF-1 plays a central role in regulating aging, both through interactions with key longevity factors including Sirtuins and mTOR, as well as by directly promoting longevity in Caenorhabditis elegans. We investigated a novel function and the underlying mechanism of syringaresinol, a lignan compound, in modulation of HIF- 1 and protection against cellular damage and death in a cardiomyocyte model of I/R injury. Syringaresinol caused destabilization of HIF-1a following H/R and then protected against hypoxia/reoxygenation (H/R)-induced cellular damage, apoptosis, and mitochondrial dysfunction in a dose-dependent manner. Knock-down of FOXO3 by specific siRNAs completely abolished the ability of syringaresinol to inhibit HIF- 1 stabilization and apoptosis caused by H/R. Syringaresinol stimulated the nuclear localization and activity of FOXO3 leading to increased expression of antioxidant genes and decreased levels of reactive oxygen species (ROS) following H/R. Our results provide a new mechanistic insight into a functional role of syringaresinol against H/R-induced cardiomyocyte injury and death. The degradation of HIF-1a through activation of FOXO3 is a potential therapeutic strategy for ischemia-related diseases.

Original languageEnglish (US)
Pages (from-to)43-55
Number of pages13
JournalOncotarget
Volume6
Issue number1
DOIs
StatePublished - 2015

Keywords

  • Cardiomyocytes
  • FOXO3
  • HIF-1a
  • Hypoxia/reoxygenation
  • Ischemia/reperfusion
  • Syringaresinol

ASJC Scopus subject areas

  • Oncology

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