XCT790通过下调雌激素相关受体α的表达抑制大鼠血管平滑肌细胞增殖

XCT790 inhibits rat vascular smooth muscle cells proliferation through down-regulating the expression of estrogen-related receptor α

为探讨雌激素相关受体a（ERRa）的特异性反向激动剂XCT790对大鼠血管平滑肌细胞（VSMCs）增殖的影响及相关分子信号传导机制，采用原代培养大鼠胸主动脉VSMCs，以胎牛血清（FBS）刺激VSMCs增殖，分别加入不同浓度的XCT790，以CCK-8试剂检测XCT790对VSMCs增殖的影响；以RT-PCR考察ERRa、PGC-la、OPN和MCAD的mRNA表达水平：以Western blotting检测ERRa、ERK2及P．ERK1／2蛋白表达水平；以ELISA法检测VEGF蛋白水平。结果显示，XCT790对VSMCs增殖的抑制作用在5～20pmol·L^-1剂量范围内呈显著剂量依赖性，在10-20lmaol·L^-1剂量范围内呈显著时间依赖性；且5～20gmol·L^-1 XCT790能明显下调ERRa与口．ERK1／2水平（P〈0．05，P〈0．01）。提示：XCT790可通过下调ERRa及其靶基因转录，进而抑制ERK途径来抑制大鼠vSMCs增殖。

Abnormal proliferation of vascular smooth muscle cells （VSMCs） plays an important role in several pathological processes of cardiovascular diseases. In this study, the effects of XCT790, a potent and selective inverse agonist of estrogen-related receptor a （ERRa）, on rat VSMCs proliferation and related signal pathways were investigated. The proliferative activity of VSMCs was determined by CCK-8 assay. The mRNA levels of ERRa, PGC-la, OPN and MCAD were assayed by RT-PCR. The protein levels of ERRa, ERK2 and p-ERK1/2 were evaluated by Western blotting. ELISA was used to assess the protein expression of VEGE The results showed that XCT790 （5-20 ~tmol＇L-1） inhibited rat VSMCs proliferation, and the expression of ERRa and its target genes, as well as p-ERK1/2, were also inhibited. XCT790 inhibited VSMCs proliferation in a dose-dependent manner at the dose range from 5 to 20 pmol-L-1 and in a time-dependent manner at the dose range from 10 to 20 ~mol-L-1. These findings demonstrate that XCT790 inhibits rat VSMCs proliferation by down-regulating the gene level of ERRa and thus inhibiting the ERK signal pathway, suggesting that ERRa may be a novel potential target for therapeutic approaches to inhibit VSMCs proliferation, which plays an important role in several cardiovascular diseases.