title: Fenofibrate decreases asymmetric dimethylarginine level in cultured endothelial cells by inhibiting NF-kappaB activity.
abstract: Previous investigations have demonstrated that endogenous inhibitors of nitric oxide synthase (NOS), such as asymmetric dimethylarginine (ADMA), contribute importantly to endothelial dysfunction, and that fenofibrate has a protective effect on the endothelium in rats treated with low-density lipoprotein (LDL) by reducing ADMA levels. In the present study, we explored further the possible mechanism underlying inhibition of ADMA generation by fenofibrate in cultured human umbilical vein endothelial cells (HUVECs). Endothelial injury was induced in cultured HUVECs by incubation with oxidative LDL (ox-LDL) and the levels of ADMA, lactate dehydrogenase (LDH), NO and tumour necrosis factor-alpha (TNF-alpha) in the conditioned medium were measured. Cell viability and the activity of dimethylarginine dimethylaminohydrolase (DDAH) and nuclear factor-kappaB (NF-kappaB) in the cultured HUVECs were also determined. Incubation of HUVECs with ox-LDL (100 microg/ml) for 24 h markedly elevated ADMA, LDH and TNF-alpha in the conditioned medium and significantly increased the activity of NF-kappaB, concomitantly with a significant decrease in the activity of DDAH and the content of NO. Pretreatment with fenofibrate (3, 10 or 30 microM) significantly inhibited the increases in ADMA, LDH and TNF-alpha, attenuated the decreased levels of NO and the decreased activity of DDAH and prevented the activation of NF-kappaB. Similar effects were observed in the presence of pyrrolidine dithiocarbamate (PDTC, 10 microM), an antagonist of NF-kappaB. The beneficial effects of fenofibrate on cultured endothelial cells were abolished by MK-886, a specific peroxisome proliferator-activated receptor-alpha (PPARalpha) antagonist. The present results suggest that fenofibrate inhibits ox-LDL-induced endothelial cell damage by decreasing ADMA and increasing DDAH activity, and the protective effects of fenofibrate on endothelial cells may be related to reduction of NF-kappaB activity by activation of the PPARalpha receptor.
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410078, China.
authors.forename: Tian-Lun
authors.initials: TL
authors.lastname: Yang
authors.forename: Mei-Fang
authors.initials: MF
authors.lastname: Chen
authors.forename: Bai-Lin
authors.initials: BL
authors.lastname: Luo
authors.forename: Qi-Ying
authors.initials: QY
authors.lastname: Xie
authors.forename: Jun-Lin
authors.initials: JL
authors.lastname: Jiang
authors.forename: Yuan-Jian
authors.initials: YJ
authors.lastname: Li
mesh_terms: D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D011345:Fenofibrate / Q000494:pharmacology*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009569:Nitric Oxide / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
chemical_list: D000960:Hypolipidemic Agents; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C487735:dimethylarginine; D009569:Nitric Oxide; D001120:Arginine; D007770:L-Lactate Dehydrogenase; D011345:Fenofibrate