title: 2-Methoxyestradiol prevents monocyte adhesion to vascular endothelial cells via downregulation of VCAM-1 expression.
abstract: 2-Methoxyestradiol (2-ME) reduces atherosclerotic lesion formation. However, the underlying mechanisms remain largely unknown. In this work, we investigated the effect of 2-ME on monocyte adhesion to vascular endothelial cells. Lipopolysaccharides (LPS) greatly increased the attachment of monocyte onto cultured human umbilical vascular endothelial cells (HUVECs), which was inhibited by 2-ME in a dose- and time-dependent manner, or by the vascular cell adhesion protein-1 (VCAM-1) neutralizing antibody, suggesting that a functional releationship between 2-ME and VCAM-1 may exist. In accordance with this, treatment with 2-ME (10(-)(7)-10(-)(5) M) for 6-48 h downregulated VCAM-1 protein expression. Meanwhile, the nuclear factor κB (NF-κB) p65 subunit activity and its nuclear translocation was inhibited by 2-ME in HUVECs. The PI3K inhibitor wortmannin or the specific Akt siRNA both inhibited the effects of 2-ME, suggesting that 2-ME inhibited p65 activity via PI3K/Akt signaling. In conclusion, 2-ME inhibits VCAM-1 expression and thus prevents monocyte adhesion to vascular endothelial cells via regulation of PI3K/Akt and NF-κB signaling. These findings will be helpful for better understanding the mechanisms through which 2-ME improves endothelial function.
authors.affiliation: a Department of Anesthesiology , Guangzhou Women and Children's Medical Center , Guangzhou, Guangdong Province , China .
authors.forename: Yongfu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: b School of Basic Sciences, Guangzhou Medical University , Guangzhou, Guangdong Province , China .
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: c Department of Anesthesiology , Longhua Hospital , Shenzhen, Guangdong Province , China , and.
authors.forename: Qi
authors.initials: Q
authors.lastname: Gao
authors.affiliation: d Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, University of Pisa , Pisa , Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Simoncini
authors.affiliation: b School of Basic Sciences, Guangzhou Medical University , Guangzhou, Guangdong Province , China .
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Fu
mesh_terms: D000077584:2-Methoxyestradiol; D002448:Cell Adhesion / Q000187:drug effects*; D002478:Cells, Cultured; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism; D042341:Gonadal Hormones / Q000378:metabolism*; D006801:Humans; D009000:Monocytes / Q000187:drug effects*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
chemical_list: D042341:Gonadal Hormones; D019010:Vascular Cell Adhesion Molecule-1; D004958:Estradiol; D000077584:2-Methoxyestradiol
keywords: 2-Methoxyestradiol; monocyte adhesion; nuclear factor κB; vascular cell adhesion molecule-1; vascular endothelial cells