| 17611319 |
Li JC, Chang L, Lu D, Jiang DJ, Tan DM: [Effect of asymmetric dimethylarginine on the activation of hepatic stellate cells and its mechanism]. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2007 Jun;32(3):427-32.
OBJECTIVE: To investigate the effect of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, on the activation of hepatic stellate cells (HSCs) and its mechanism. METHODS: Primary HSCs isolated from SD rats were cultured and treated with different concentrations (1, 3 or 10micromol/L) of ADMA for various periods (12 approximately 48h). Expression of alpha-smooth muscle actin (alpha-SMA) and synthesis of type-I collagens in HSC were determined. Messenger RNA levels of the transforming growth factor-beta1 (TGF-beta (1)) in the HSCs were determined using RT-PCR. Intracellular reactive oxidant species (ROS) production was measured using oxidant-sensitive fluorescent indicator. Activation of nuclear factor-kappaB (NF-kappaB) was detected by electrophoretic mobility shift assay (EMSA). RESULTS: ADMA could increase alpha-SMA-positive cells ratio and Type I collagens production of HSCs in a concentration- and time-dependent manner, concomitant with the increase of the TGF-beta (1) mRNA level. Treatment with ADMA (10micromol/L) significantly increased the intracellular ROS production and activated NF-kappaB. Such effects of ADMA on the level of TGF-beta (1) mRNA could be markedly attenuated by pretreatment with antioxidant pyrrolidine dithiocarbamate (25micromol/L). CONCLUSION: ADMA can induce the HSC activation by increasing TGF-beta (1) expression through ROS-NF-kappaB-dependent pathway. Therefore, ADMA should be a novel and endogenous activator of HSC, which may be involved in the development of liver fibrosis. |
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