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An aryl hydrocarbon receptor agonist suppresses the growth of human umbilical vein endothelial cells in vitro: Potent effect with polyunsaturated fatty acids
Author(s) -
Yamaguchi Masayoshi,
Hankinson Oliver
Publication year - 2020
Publication title -
international journal of experimental pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.671
H-Index - 72
eISSN - 1365-2613
pISSN - 0959-9673
DOI - 10.1111/iep.12373
Subject(s) - aryl hydrocarbon receptor , umbilical vein , polyunsaturated fatty acid , in vitro , agonist , chemistry , aryl , receptor , biochemistry , pharmacology , fatty acid , biology , organic chemistry , gene , alkyl , transcription factor
Summary Human umbilical vein endothelial cells (HUVECs) are a pivotal component of the hematopoietic microenvironment linked to the modulation of the immune response, inflammation and carcinogenesis. HUVEC expresses the aryl hydrocarbon receptor (AHR), which regulates gene expression by binding to the xenobiotic‐responsive element. 2,3,7,8‐Tetrachlorodibenzo‐ p ‐dioxin (TCDD) is a potent agonist for AHR signalling. Treatment with TCDD (0.1‐100 nmol/L) was found to suppress the proliferation and to stimulate the death of HUVEC. TCDD’s effects were abolished by culturing with CH223191, an inhibitor of AHR signalling. Mechanistically, TCDD treatment increased the protein levels of cell growth suppressors, including p53, Rb, p21 and regucalcin, and caspase‐3 implicated in apoptotic cell death, and decreased the levels of Stat3, mitogen‐activated protein kinase (MAPK/Erk1/2) and phospho‐MAPK/Erk1/2. Treatment with polyunsaturated fatty acids (PUFAs), including docosahexaenoic acid, eicosapentaenoic acid and arachidonic acid, suppressed the proliferation and stimulated the death of HUVEC in vitro, and decreased the levels of Stat3, MAPK/Erk1/2 and phospho‐MAPK/Erk1/2 and increased caspase‐3. Notably, the effects of TCDD in suppressing proliferation and stimulating death of HUVEC were modulated by coculturing with PUFAs. These effects were reversed by treatment with CH223191, an inhibitor of AHR. Treatment with both TCDD and PUFAs collaboratively enhanced the levels of AHR, CYP1A1, p53, p21, Rb and regucalcin. Moreover, TCDD suppressed migration with wound healing of HUVEC. Notably, the combination of TCDD and PUFAs revealed potent suppressive effects on angiogenesis of HUVEC, potentially related to disorders of the stromal microenvironment.