title: Asymmetric dimethylarginine damages connexin43-mediated endothelial gap junction intercellular communication.
abstract: Asymmetric dimethylarginine (ADMA), a major endogenous inhibitor of nitric oxide synthase, is recently defined as a novel atherogenic factor. Communication via gap junction (GJIC) is involved in the regulation of a variety of endothelial activities, such as cell differentiation and senescence. The aim of this study is to explore the effects of ADMA on connexin43 (Cx43) mediated endothelial GJIC. Lysophosphatidylcholine (LPC) caused the downregulation of Cx43 expression and GJIC dysfunction in cultured human umbilical vein endothelial cells (HUVECs), which were significantly ameliorated by decreasing ADMA accumulation. Furthermore, we found that ADMA (10 micromol x L(-1), 24 h) markedly downregulated Cx43 expression and damaged GJIC function in HUVECs. ADMA also increased production of intracellular reactive oxygen species (ROS) and induced phosphorylation of p38 MAPK. Furthermore, the inhibitory effect of ADMA on Cx43-mediated GJIC could be attenuated by NADPH oxidase inhibitor diphenyleneiodonium and apocynin as well as p38 MAPK inhibitor SB203580, respectively. In conclusion, our present results suggest that ADMA inhibits endothelial GJIC function via downregulating Cx43 expression, which suggesting a novel mechanism linking between elevated ADMA level and progression of atherosclerosis.
authors: Department of Pharmaceutics, The Third XiangYa Hospital of Central South University, Changsha, China.
authors: Su-Jie
authors: SJ
authors: Jia
authors: Zhi
authors: Z
authors: Zhou
authors: Bi-Kui
authors: BK
authors: Zhang
authors: Zhuo-Wei
authors: ZW
authors: Hu
authors: Han-Wu
authors: HW
authors: Deng
authors: Yuan-Jian
authors: YJ
authors: Li
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology*; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism*; D036681:Fluorescence Recovery After Photobleaching; D017629:Gap Junctions / Q000378:metabolism*; D006801:Humans; D008244:Lysophosphatidylcholines / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018031:Connexin 43; D004791:Enzyme Inhibitors; D008244:Lysophosphatidylcholines; D017382:Reactive Oxygen Species; C018524:N,N-dimethylarginine; D001120:Arginine; D019255:NADPH Oxidases; D048051:p38 Mitogen-Activated Protein Kinases; D000581:Amidohydrolases; C059999:dimethylargininase