Fenofibrate decreases asymmetric dimethylarginine level in cultured endothelial cells by inhibiting NF-κB activity

被引:41
作者
Yang, TL
Chen, MF
Luo, BL
Xie, QY
Jiang, JL
Li, YJ
机构
[1] Cent S Univ, Sch Pharmaceut Sci, Dept Pharmacol, Changsha 410078, Hunan, Peoples R China
[2] Cent S Univ, Xiang Ya Hosp, Dept Cardiovasc Med, Changsha 410008, Hunan, Peoples R China
关键词
fenofibrate; oxidative low-density lipoprotein (ox-LDL); asymmetric dimethylarginine (ADMA); dimethylarginine dimethylaminohydrolase (DDAH); nuclear factor-kappa B (NF-kappa B); tumour necrosis factor-alpha (TNF-alpha);
D O I
10.1007/s00210-005-1060-8
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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-kappa B (NF-kappa B) in the cultured HUVECs were also determined. Incubation of HUVECs with ox-LDL (100 mu g/ml) for 24 h markedly elevated ADMA, LDH and TNF-alpha in the conditioned medium and significantly 886, a specific peroxisome proliferator-activated receptor-a (PPAR alpha) antagonist. The present results suggest that feno-fibrate 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-kappa B activity by activation of the PPARa receptor.increased the activity of NF-kappa B, concomitantly with a significant decrease in the activity of DDAH and the content of NO. Pretreatment with fenofibrate ( 3, 10 or 30 mu M) 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-kappa B. Similar effects were observed in the presence of pyrrolidine dithiocarbamate (PDTC, 10 mu M), an antagonist of NF-kappa B. The beneficial effects of fenofibrate on cultured endothelial cells were abolished by MK-886, a specific peroxisome proliferator-activated receptor-a (PPAR alpha) antagonist. The present results suggest that feno-fibrate 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-kappa B activity by activation of the PPARa receptor.
引用
收藏
页码:401 / 407
页数:7
相关论文
共 38 条
[1]  
BESSMAN JD, 1983, SURG GYNECOL OBSTET, V156, P177
[2]   An endogenous inhibitor of nitric oxide synthase regulates endothelial adhesiveness for monocytes [J].
Böger, RH ;
Bode-Böger, SM ;
Tsao, PS ;
Lin, PS ;
Chan, JR ;
Cooke, JP .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2000, 36 (07) :2287-2295
[3]   LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells -: Involvement of S-adenosylmethionine-dependent methyltransferases [J].
Böger, RH ;
Sydow, K ;
Borlak, J ;
Thum, T ;
Lenzen, H ;
Schubert, B ;
Tsikas, D ;
Bode-Böger, SM .
CIRCULATION RESEARCH, 2000, 87 (02) :99-105
[4]   Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in monkeys with hyperhomocyst(e)inemia or hypercholesterolemia [J].
Böger, RH ;
Bode-Böger, SM ;
Sydow, K ;
Heistad, DD ;
Lentz, SR .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2000, 20 (06) :1557-1564
[5]   The emerging role of asymmetric dimethylarginine as a novel cardiovascular risk factor [J].
Böger, RH .
CARDIOVASCULAR RESEARCH, 2003, 59 (04) :824-833
[6]   An animal model to study local oxidation of LDL and its biological effects in the arterial wall [J].
Calara, F ;
Dimayuga, P ;
Niemann, A ;
Thyberg, J ;
Diczfalusy, U ;
Witztum, JL ;
Palinski, W ;
Shah, PK ;
Cercek, B ;
Nilsson, J ;
Regnström, J .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 1998, 18 (06) :884-893
[7]  
Canty TG, 1999, CIRCULATION, V100, P361
[8]   Asymmetric dimethylarginine increases mononuclear cell adhesiveness in hypercholesterolemic humans [J].
Chan, JR ;
Böger, RH ;
Bode-Böger, SM ;
Tangphao, O ;
Tsao, PS ;
Blaschke, TF ;
Cooke, JP .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2000, 20 (04) :1040-1046
[9]   Determination of N-G,N-G-dimethylarginine in human plasma by high-performance liquid chromatography [J].
Chen, BM ;
Xia, LW ;
Zhao, RQ .
JOURNAL OF CHROMATOGRAPHY B, 1997, 692 (02) :467-471
[10]   NF-κB:: pivotal mediator or innocent bystander in atherogenesis? [J].
Collins, T ;
Cybulsky, MI .
JOURNAL OF CLINICAL INVESTIGATION, 2001, 107 (03) :255-264