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.
Highlights
Proper adaptation to endogenous and exogenous stressors is critical for cells and organisms to survive [1]
Since lactate dehydrogenase (LDH) leakage is widely used as a marker of cellular damage, cardiomyocyte cells injury was assessed by determining LDH activity in culture medium at the end of reoxygenation
Our results indicate that FOXO3 plays an important role in mediating the protective effects of syringaresinol for cardiomyocytes cell line subjected to H/R through modulation of hypoxiainducible factor (HIF)-1α stability and its target gene expression
Summary
Proper adaptation to endogenous and exogenous stressors is critical for cells and organisms to survive [1]. Short-term exposure to reduced oxygen availability can lead to a beneficial metabolic adaptation associated with increased cellular and organismal survival [4,5,6], while prolonged exposure of cells to hypoxia leads to DNA damage, cell death, and contributes to many diseases including diabetes, atherosclerosis and cardiovascular diseases (CVD) [7]. The primary system for adapting to low oxygen levels is the hypoxic response pathway [9,10,11]. A key www.impactjournals.com/oncotarget player in this pathway is the hypoxia induction factor 1 (HIF-1), a master regulator of the response to hypoxia that regulates the expression of a broad range of genes that facilitate the adaptation to, and survival of cells to low oxygen environments [12, 13]. The hydroxylation modification declines and HIF-1α is stabilized for its transcriptional activities [15]
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