title: Syringaresinol protects against hypoxia/reoxygenation-induced cardiomyocytes injury and death by destabilization of HIF-1α in a FOXO3-dependent mechanism.
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.
authors.affiliation: R&D Unit, Amorepacific Corporation, Yongin-si, Gyeonggi-do, Korea.
authors.forename: Siyoung
authors.initials: S
authors.lastname: Cho
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Miook
authors.initials: M
authors.lastname: Cho
authors.affiliation: R&D Unit, Amorepacific Corporation, Yongin-si, Gyeonggi-do, Korea.
authors.forename: Juewon
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Kaeberlein
authors.affiliation: R&D Unit, Amorepacific Corporation, Yongin-si, Gyeonggi-do, Korea.
authors.forename: Sang Jun
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Yousin
authors.initials: Y
authors.lastname: Suh
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death; D015687:Cell Hypoxia; D002460:Cell Line; D002470:Cell Survival; D005434:Flow Cytometry; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005663:Furans / Q000737:chemistry*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D017705:Lignans / Q000737:chemistry*; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology*; D010100:Oxygen / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D005663:Furans; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017705:Lignans; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C042192:syringaresinol; C505410:Casp3 protein, rat; D053148:Caspase 3; D010100:Oxygen