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Oncotarget. 2015 Jan 1;6(1):43-55.

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

Author information

1
R&D Unit, Amorepacific Corporation, Yongin-si, Gyeonggi-do, Korea.
2
Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
3
Department of Pathology, University of Washington, Seattle, WA, USA.
4
Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA. Department of Medicine, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, NY, USA. Institute for Aging Research, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, NY, USA.

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-1α 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-1α through activation of FOXO3 is a potential therapeutic strategy for ischemia-related diseases.

PMID:
25415049
PMCID:
PMC4381577
DOI:
10.18632/oncotarget.2723
[Indexed for MEDLINE]
Free PMC Article

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