title: Melatonin suppresses hypoxia-induced migration of HUVECs via inhibition of ERK/Rac1 activation.
abstract: Melatonin, a naturally-occurring hormone, possesses antioxidant properties and ameliorates vascular endothelial dysfunction. In this study, we evaluate the impact of melatonin on the migratory capability of human umbilical vein endothelial cells (HUVECs) to hypoxia and further investigate whether ERK/Rac1 signaling is involved in this process. Here, we found that melatonin inhibited hypoxia-stimulated hypoxia-inducible factor-1α (HIF-1α) expression and cell migration in a dose-dependent manner. Mechanistically, melatonin inhibited Rac1 activation and suppressed the co-localized Rac1 and F-actin on the membrane of HUVECs under hypoxic condition. In addition, the blockade of Rac1 activation with ectopic expression of an inactive mutant form of Rac1-T17N suppressed HIF-1α expression and cell migration in response to hypoxia, as well, but constitutive activation of Rac1 mutant Rac1-V12 restored HIF-1α expression, preventing the inhibition of melatonin on cell migration. Furthermore, the anti-Rac1 effect of melatonin in HUVECs appeared to be associated with its inhibition of ERK phosphorylation, but not that of the PI3k/Akt signaling pathway. Taken together, our work indicates that melatonin exerts an anti-migratory effect on hypoxic HUVECs by blocking ERK/Rac1 activation and subsequent HIF-1α upregulation.
authors.affiliation: Department of Cardiology, the Third Affiliated Hospital of Soochow University, Changzhou 213003, Jiangsu, China. Linda_YL73@yahoo.com.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, Jiangsu, China. zhjch@njmu.edu.cn.
authors.forename: Jianchao
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, Jiangsu, China. xurui20062624@gmail.com.
authors.forename: Rui
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, Jiangsu, China. zhangyujie@njmu.edu.cn.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, Jiangsu, China. lgu@njmu.edu.cn.
authors.forename: Luo
authors.initials: L
authors.lastname: Gu
authors.affiliation: Epidemiology and Biostatistics and Ministry of Education (MOE) Key Lab for Modern Toxicology, Nanjing Medical University, Nanjing 210029, Jiangsu, China. cindydongjing@gmail.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Dong
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, Jiangsu, China. zhuyichao@njmu.edu.cn.
authors.forename: Yichao
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Cardiology, the Third Affiliated Hospital of Soochow University, Changzhou 213003, Jiangsu, China. ruijuezhoucz@yahoo.com.
authors.forename: Ruijue
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Comprehensive Laboratory, the Third Affiliated Hospital of Soochow University, Changzhou 213003, Jiangsu, China. luzhengcz@yahoo.com.
authors.forename: Lu
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Comprehensive Laboratory, the Third Affiliated Hospital of Soochow University, Changzhou 213003, Jiangsu, China. xiaoyingzhangcz@yahoo.com.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, Jiangsu, China. dujun@njmu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Du
mesh_terms: D000199:Actins / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008550:Melatonin / Q000494:pharmacology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000199:Actins; D048049:Extracellular Signal-Regulated MAP Kinases; D020830:rac1 GTP-Binding Protein; D008550:Melatonin