期刊
TOXICOLOGICAL SCIENCES
卷 102, 期 2, 页码 319-327出版社
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfn003
关键词
arsenic; alcohol; endothelial; angiogenesis; cell signaling
类别
资金
- NIEHS NIH HHS [R01ES013781] Funding Source: Medline
Arsenic in the drinking water may promote vascular diseases in millions of people worldwide through unresolved mechanisms. In addition, little is known of the effects of coexposures to arsenic and other common vasculature toxicants, such as alcohol. To investigate signaling interactions between arsenic and alcohols, primary human microvascular endothelial (HMVEC) cells were exposed to noncytotoxic concentrations of arsenite (1-5 mu M) in the presence or absence of 0.1% ethanol (EtOH). Coexposure, but not exposure to either agent alone, rapidly increased active Fyn tyrosine kinase, tyrosine phosphorylation of a 109-kDa protein and serine phosphorylation of protein kinase C (PKC)delta. The 109-kDa protein was identified as PYK2, a regulator of vascular integrin signaling and an upstream activator of PKC delta. Membrane localization of phospholipase C gamma 1 was increased by coexposure within 15 min, but not by either agent alone. In contrast, both agents equally increased membrane localization of Rac1-GTPase. Coexposure, but not exposure to either agent alone, induced transcript levels for the angiogenic genes, vascular endothelial cell growth factor (Vegfa) and insulin-like growth factor-1 (Igf1). However, EtOH inhibited arsenic-induced, nuclear factor-kappa B-driven interleukin-8 and collagen-1 expression. Differential effects of selective PKC inhibitors on induced gene expression combined with a lack of interaction for induction of hemeoxygenase-1 further demonstrated that arsenic-responsive signaling pathways differ in sensitivity to EtOH interactions. Finally, coexposure enhanced endothelial tube formation in in vitro angiogenesis assays. These data indicate that complex interactions occur between arsenic and EtOH exposures that functionally affect endothelial signaling for gene induction and remodeling stimuli.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据