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Int. J. Mol. Sci. 2014, 15(8), 14102-14121; doi:10.3390/ijms150814102

Melatonin Suppresses Hypoxia-Induced Migration of HUVECs via Inhibition of ERK/Rac1 Activation

1
Department of Cardiology, the Third Affiliated Hospital of Soochow University, Changzhou 213003, Jiangsu, China
2
Department of Physiology, Nanjing Medical University, Nanjing 210029, Jiangsu, China
3
Epidemiology and Biostatistics and Ministry of Education (MOE) Key Lab for Modern Toxicology, Nanjing Medical University, Nanjing 210029, Jiangsu, China
4
Comprehensive Laboratory, the Third Affiliated Hospital of Soochow University, Changzhou 213003, Jiangsu, China
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 5 April 2014 / Revised: 31 July 2014 / Accepted: 7 August 2014 / Published: 13 August 2014
(This article belongs to the Special Issue Advances in the Research of Melatonin 2014)
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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. View Full-Text
Keywords: hypoxia; ERK; Rac1; HIF-1α; migration; HUVEC; melatonin hypoxia; ERK; Rac1; HIF-1α; migration; HUVEC; melatonin
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Yang, L.; Zheng, J.; Xu, R.; Zhang, Y.; Gu, L.; Dong, J.; Zhu, Y.; Zhou, R.; Zheng, L.; Zhang, X.; Du, J. Melatonin Suppresses Hypoxia-Induced Migration of HUVECs via Inhibition of ERK/Rac1 Activation. Int. J. Mol. Sci. 2014, 15, 14102-14121.

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