Research Papers: Gerotarget (Focus on Aging):
GDF15 contributes to radiation-induced senescence through the ROS-mediated p16 pathway in human endothelial cells
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Hyejin Park1, Chun-Ho Kim1, Jae-Hoon Jeong2, Myungjin Park3,* and Kwang Seok Kim1,*
1 Divisions of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
2 Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
3 Divisions of Radiation Cancer Science, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea
* These authors have contributed equally to this work
Kwang Seok Kim, email:
Myungjin Park, email:
Keywords: cellular senescence, ionizing radiation, p53, p16, endothelilal cells, oxidative stress, Gerotarget
Received: December 03, 2015 Accepted: February 09, 2016 Published: February 17, 2016
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.
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