Prevention of Nitric Oxide Production and Cell Deaths by Estrogen in Estrogen Receptor Expressed Rheumatoid Arthritis Fibroblasts

我们进行了一系列实验，假设RA的发病最初是由线粒体产生ROS并与NO结合导致脂质过氧化和随后的细胞凋亡引起的。此外，我们还推测雌激素调节线粒体ROS和NO的生成及脂质过氧化是抑制RA滑膜成纤维细胞凋亡的潜在因素，这些作用依赖于ER的表达。本研究表明：(1)在RA中，线粒体ROS和NO可能通过增加脂质过氧化和细胞凋亡而成为RA发病的关键因素；(2)雌激素及其与ER的结合通过控制滑膜成纤维细胞线粒体ROS和NO及脂质过氧化的生成，在保护细胞免受细胞因子诱导的细胞凋亡中发挥重要作用；(3)ER_2的差异表达导致不同世代的线粒体ROS、NO、脂质过氧化及随后的细胞凋亡。这些结果支持了滑膜成纤维细胞线粒体内ROS和NO的生成和脂质过氧化产物的产生随后加速细胞死亡的假说，它们是通过雌激素与滑膜成纤维细胞中的ER_2结合来调节的。

We performed a series of experiments hypothesizing that pathogenesis of RA is initially caused by generations of ROS from mitochondria and binding with NO results in lipid peroxidation and subsequent apoptosis. In addition we hypothesized that estrogen regulates mitochondrial ROS and NO productions and lipid peroxidation as a potential factors for the inhibition of apoptosis in synovial fibroblasts in RA, and these effects were dependent on the expressions of ERs.This study indicated that (1)in RA, mitochondrial ROS and NO would be key players to cause RA pathogenesis by subsequent increase in lipid peroxidation and apoptosis ; (2)estrogen and the binding to ER plays an important role in protecting cells against cytokine-induced apoptotic cell death by controlling the generations of mitochondrial ROS and NO and lipid peroxidation in synovial fibroblasts ; (3)the differential expression of ER_results in different generations of mitochondrial ROS, NO, lipid peroxidation and subsequent apoptosis. These results support the overall hypothesis that intracellular mitochondrial ROS and NO generations and production of lipid peroxidation products subsequently accelerates apoptotic cell death and they are regulated by binding of estrogen to ER_in synovial fibroblasts.