Medical College of Wisconsin
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Melatonin suppresses hypoxia-induced migration of HUVECs via inhibition of ERK/Rac1 activation. Int J Mol Sci 2014 Aug 13;15(8):14102-21

Date

08/16/2014

Pubmed ID

25123138

Pubmed Central ID

PMC4159841

DOI

10.3390/ijms150814102

Scopus ID

2-s2.0-84930697024 (requires institutional sign-in at Scopus site)   30 Citations

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.

Author List

Yang L, Zheng J, Xu R, Zhang Y, Gu L, Dong J, Zhu Y, Zhou R, Zheng L, Zhang X, Du J

Author

Jing Dong PhD Assistant Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Actins
Cell Hypoxia
Cell Movement
Extracellular Signal-Regulated MAP Kinases
Human Umbilical Vein Endothelial Cells
Humans
Melatonin
rac1 GTP-Binding Protein