Role of asymmetric dimethylarginine in inflammatory reactions by angiotensin II.

Previous investigations have demonstrated that angiotensin (Ang) II induces inflammatory reactions and asymmetric dimethylarginine (ADMA), an endogenous NOS inhibitor, might be a novel inflammatory factor. Endothelial cell activation was induced by incubation with Ang II or ADMA. Incubation with Ang II (10(-6) M) for 24 h elevated the levels of ADMA and decreased the levels of nitrite/nitrate concomitantly with a significant increase in the expression of protein arginine methyltransferase and a decrease in the activity of dimethylarginine dimethylaminohydrolase (DDAH). Exposure to Ang II (10(-6) M for 24 h) also enhanced intracellular ROS elaboration and the levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-8, upregulated chemokine receptor CXCR2 mRNA expression, increased adhesion of endothelial cells to monocytes and induced a significant increase in the activity of nuclear factor (NF)-kappaB, which was attenuated by pretreatment with the Ang II receptor blocker losartan (1, 3 and 10 muM). Exogenous ADMA (30 microM) also increased ROS generation and the levels of TNF-alpha and IL-8, decreased the levels of nitrite/nitrate, upregulated CXCR2 gene expression, increased endothelial cell binding with monocytes and activated the NF-kappaB pathway, which was inhibited by pretreatment with losartan or L-arginine. These data suggest that ADMA is a potential proinflammatory factor and may be involved in the inflammatory reaction induced by Ang II.

Effect of fenofibrate on the level of asymmetric dimethylarginine in individuals with hypertriglyceridemia.

OBJECTIVE: To test whether treatment with fenofibrate decreases asymmetric dimethylarginine (ADMA) level in hypertriglyceridemic individuals. METHODS: In the present study, 45 subjects with hypertriglyceridemia were recruited to receive treatment with fenofibrate (200 mg/d). Serum concentrations of ADMA, malondialdehyde (MDA), nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) were measured. Endothelial function assessed by flow-mediated dilation (FMD) of the brachial artery was performed. RESULTS: Compared with control, serum levels of ADMA (0.47+/-0.05 micromol/L in control and 0.62+/-0.28 micromol/L in hypertriglyceridemic patients, P<0.01), MDA and TNF-alpha were markedly elevated, and the level of NO was significantly reduced, concomitantly with impaired endothelium-dependent vasodilation in individuals with hypertriglyceridemia. 8-week treatment with fenofibrate significantly reduced the elevated levels of ADMA (0.53+/-0.12 micromol/L, P<0.01), MDA and TNF-alpha, attenuated the decreased level of NO and improved endothelial function. CONCLUSIONS: These results suggest that the beneficial effect of fenofibrate on the endothelium in hypertriglyceridemic individuals may be related to reduction of ADMA level.

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

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.