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Effect of Asymmetric Dimethylarginine on Fibrinolytic Factors and the Cellular Mechanismsin Vascular Endothelium

Author: ZhangQin
Tutor: JinHong
School: Shantou University
Course: Cardiovascular within science
Keywords: Asymmetric dimethylarginine (ADMA) tissue plasminogen activator (tPA) plasminogen activator inhibitor-1 (PAI-1) mitogen activated protein kinase (MAPK) nuclear factor-kappaB (NF-κB)
CLC: R54
Type: Master's thesis
Year: 2010
Downloads: 40
Quote: 0
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Abstract


BackgroundAsymmetric dimethylarginine (ADMA), a potent endogenous inhibitor of nitric oxide synthase (NOS), induces endothelial dysfunction via inhibiting nitric oxide (NO) production. An increased synthesis and / or a reduced catabolism of ADMA might contribute to the onset and progression of thrombotic complications. The mechanism, however, is far from elucidated.ObjectiveThe aim of the present study was to evaluate the impact of ADMA on the expression of main fibrinolytic factors, including tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1), in cultured vascular endothelial cells; and the study was designed to observe the contributions of various signal pathways to ADMA induced fibrinolytic factors` expression, so to investigate the effect of ADMA on fibrinolytic activities and its cellular mechanisms.Methods(1) Human umbilical vein endothelial cells (HUVEC) within 3-5 passages were treated with culture medium only (con), or different concentrations of ADMA (3, 10, 30μmol/L) for various periods (6, 24, 48h); (2) HUVEC were divided to control group, ADMA group, NO precursor (ι-arginine) pretreatment with ADMA group, or MAPKs (ERK1/2, JUN and p38 MAPK) inhibitors pretreatment with ADMA group, and NF-κB inhibitor (PDTC) pretreatment with ADMA group, respectively. The supernatant protein levels of tPA and PAI-1, and NF-κB DNA-binding activity were measured by enzyme-linked immunosorbent assay (ELISA); mRNA levels of tPA and PAI-1 were assayed by quantitative real time RT-PCR; The activation of MAPK was characterized by western blot analysis.Results(1) ADMA decreased tPA antigen levels in cultured HUVEC in time-and concentration-dependent manners, with the maximum effect of 30μmol/L ADMA treatment for 48h (control group 109.01±4.15ng/ml vs ADMA treatment group 86.76±5.95ng/ml, p<0.01); 30μmol/L ADMA treatment for 48h significantly decreased tPA mRNA levels. (2) 30μmol/L ADMA elevated PAI-1 antigen levels in a time-dependent manner, with the maximum effect of 30μmol/L ADMA treatment for 48h (control group 2721.12±278.02ng/ml vs ADMA treatment group 3435.78±22.33ng/ml, p<0.05); 30μmol/L ADMA treatment for 48h obviously upregulated PAI-1 mRNA levels. (3)ι-arginine (NO precursor), SB203580 (p38 MAPK inhibitor) and PDTC (NF-κB inhibitor) attenuated the effects of ADMA (30μmol/L) on tPA and PAI-1 dramatically. (4) Moreover, 30μmol/L ADMA induced a rapid phosphorylation of p38 MAPK, and greatly stimulated NF-κB DNA-binding activity in HUVEC.ConclusionOur study suggests that ADMA may aggravate thrombosis development by impairing fibrinolytic activity balance in vascular via inhibiting nitric oxide production, then via p38 MAPK and NF-κB dependent pathways.

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