Effects Of Artesunate On Atherosclerosis-related Factors In Patients With Systemic Lupus Erythematosus

Objective1) To find out the relationship between atherosclerosis-related factors (MIF and VEGF) and disease activity as well as tranditional atherosclerotic risk factors in patients with systemic lupus erythematosus (SLE).2) To investigate the effect of artesunate on the regulation of these factors and to elucidate its potential mechanisms.Methods1. Clinical data were obtained from 35 SLE patients, with their SLEDAI scores and estimated 10-year risks of developing Hard CHD (Myocardial Infarction and Coronary Death) calculated. Serum levels of VEGF and MIF were measured by ELISA and expressions of interferon inducible genes were detected by real-time PCR. Whether patients with SLEDAI score >7 or estimated 10-year risks≥0.01 had abnoraml level of VEGF, MIF and interferon score were tested. And analysis the correlation between 10-year CHD risk and SLEDAI.2. Peripheral blood mononuclear cells (PBMC) were collected from 7 SLE patients. Each PBMC sample was divided into two groups:1) 5μmol/L ART treatment,2) control. After culturing for 12 hours, cells were harvested and total RNA was extracted and reverse transcribed into cDNA. Real-time PCR technique was used to determine the expressions of ISG15 and LY6E (two major IFN inducible genes) at transcription level. The levels of VEGF and MIF in supernatant were evaluated by ELISA.3. Human umbilical vein endothelial cells (HUVEC) were treated by ART at a dose of 5 or 20μmol/L or treated by dexamethasone as a positive control after exposure to IFN-α-1b 6,12 or 24hours. Real-time PCR was used to determine the gene expressions of ISG15 and LY6E at transcription level, and the levels of VEGF and MIF in supernatant were evaluated by ELISA.Results1. Compared with patients having SLEDAI score< 7, those with high scoress had significantly increased MIF levels and IFN scores, but decreased VEGF level. There were no differences between SLE patients with high and low 10-year CHD risk in the levels of MIF, VEGF and IFN score. There was a weak correlation between 10 year CHD risk and the SLEDAI score in SLE patients (r=0.365, p<0.05).2. The expression levels of ISG15 and LY6E mRNA in SLE patients were significantly decreased in ART group as compared to those in normal controls (P< 0.05), so were MIF and VEGF levels (P< 0.001).3. After stimulated with IFN 6,12 and 24 hours, the expressions of ISG15 and LY6E mRNA in HUVEC cells were significantly increased compared with controls (P< 0.05), so was MIF level (P< 0.05),whileVEGF level was significantly decreased (P< 0.05). In HUVEC cells pretreated with IFN for 12 hours, similar to dexamethasone, ART significantly decreased the expressions of ISG15,LY6E,VEGF and MIF as compare to controls(P< 0.05), and there were no significant difference between dexamethasone group and ART group. Without interferon stimulation, the expressions of LY6E and ISG15 in ART group and dexamethasone group were significantly decreased compared with those in control group (P<0.05), so were VEGF and MIF levels (P<0.05 or>0.05).Conclusions:1. Atherosclerosis related factors (MIF and VEGF) in SLE patients are related to the disease itself and its activities, but not thetraditional risk factors for atherosclerosis, suggesting that disease activity play a mojor role in the process of atherosclerosis in lupus.2. ART is able to inhibit the expression of interferon-inducible genes and decrease the secretion of VEGF and MIF in SLE patients.3. Artesunate can reduce the expression of interferon induced genes and correspondingly secretion of VEGF and MIFin HUVEC, confirming that artesunate may have therapeutic effect on the modulating of atherosclerosis related factors in SLE patients.