title: GDF15 contributes to radiation-induced senescence through the ROS-mediated p16 pathway in human endothelial cells.
abstract: Growth differentiation factor 15 (GDF15) is an emerging biomarker of cardiovascular risk and disease. Microarray analyses revealed that GDF15 levels were increased during cellular senescence induced by ionizing radiation (IR) in human aortic endothelial cells (HAECs). However, the role of GDF15 in HAEC cellular senescence remains unclear. This study demonstrated that downregulation of GDF15 in HAECs partially prevented cellular senescence triggered by IR, which was confirmed by recovery of cell proliferation and reverse senescence-associated β-galactosidase (SA-β-gal) staining. Conversely, upregulation of GDF15-induced cellular senescence in HAECs, confirmed by G0/G1 cell cycle arrest, decreased during cell proliferation and increased SA-β-gal staining. GDF15-induced cellular senescence was observed in p16-knockdown cells but not in p53-knockdown cells. GDF15 expression in endothelial cells also generated reactive oxygen species (ROS), which led to activation of extracellular signal-regulated kinases (ERKs) and induction of senescence by oxidative stress. These results suggested that GDF15 might play an important role in cellular senescence through a ROS-mediated p16 pathway and contribute to the pathogenesis of atherosclerosis via pro-senescent activity.
authors.affiliation: Divisions of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Hyejin
authors.initials: H
authors.lastname: Park
authors.affiliation: Divisions of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Chun-Ho
authors.initials: CH
authors.lastname: Kim
authors.affiliation: Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Divisions of Radiation Cancer Science, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Myungjin
authors.initials: M
authors.lastname: Park
authors.affiliation: Divisions of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Kwang Seok
authors.initials: KS
authors.lastname: Kim
mesh_terms: D001011:Aorta / Q000166:cytology / Q000528:radiation effects*; D050197:Atherosclerosis / Q000473:pathology*; D002460:Cell Line; D049109:Cell Proliferation / Q000528:radiation effects; D016922:Cellular Senescence / Q000528:radiation effects*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000528:radiation effects; D055436:Growth Differentiation Factor 15 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018384:Oxidative Stress; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011839:Radiation, Ionizing; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D048049:Extracellular Signal-Regulated MAP Kinases; D001616:beta-Galactosidase
keywords: Gerotarget; cellular senescence; endothelilal cells; ionizing radiation; oxidative stress; p16; p53