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

// Siyoung Cho 1 , Miook Cho 2 , Juewon Kim 1 , Matt Kaeberlein 3 , Sang Jun Lee 1 and Yousin Suh 2,4,5 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 Medicine, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, NY, USA 5 Institute for Aging Research, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, NY, USA Correspondence: Sang Jun Lee, email: // Yousin Suh, email: // Keywords : HIF-1α, Syringaresinol, FOXO3, ischemia/reperfusion, hypoxia/reoxygenation, cardiomyocytes Received : August 28, 2014 Accepted : November 06, 2014 Published : November 06, 2014 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.