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 language | English (US) |
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Pages (from-to) | 43-55 |
Number of pages | 13 |
Journal | Oncotarget |
Volume | 6 |
Issue number | 1 |
DOIs | |
State | Published - 2015 |
Keywords
- Cardiomyocytes
- FOXO3
- HIF-1a
- Hypoxia/reoxygenation
- Ischemia/reperfusion
- Syringaresinol
ASJC Scopus subject areas
- Oncology