AT1 receptor agonistic antibodies from preeclamptic patients stimulate NADPH oxidase
AT1 receptor agonistic antibodies from preeclamptic patients stimulate NADPH oxidase
复制标题
DOI：
10.1161/01.cir.0000058200.90059.b1
复制
发表时间：
2003-04-01
期刊：
影响因子：
37.8
通讯作者：
Luft, FC
中科院分区：
文献类型：
--
作者：
Dechend, R;Viedt, C;Luft, FC
背景-我们最近在先兆子痫妇女的血浆中发现了针对血管紧张素AT 1受体（AT（1）-AA）的激动性自身抗体。为了进一步阐明它们的作用，我们研究了AT（1）-AA对活性氧（ROS）、NADPH氧化酶表达和核因子-κ B（NF-κ B）活化的影响。方法和结果-我们研究了人血管平滑肌细胞（VSMC）和滋养层细胞以及胎盘。从子痫前期妇女血清中分离AT（1）-AA。蛋白质印迹显示血管紧张素II（Ang II）和AT（1）-AA增加ROS的产生和NADPH氧化酶组分p22、p47和p67 phox。我们接下来测试AT（1）-AA是否导致VSMC和滋养层细胞中NF-κ B的激活。AT（1）-AA激活NF-κ B。AT（1）-AA可降低抑制剂-κ B α（I-kappaB α）的表达。用氯沙坦、二亚苯基碘鎓盐、泰隆和反义p22 phox阻断AT 1受体均降低ROS产生和NF-κ B活化。p47 phox-/-小鼠的VSMC对Ang II和AT（1）-AA的反应显示ROS生成和NF-κ B活化显著减少。与正常胎盘相比，先兆子痫患者胎盘中p22、p47和p67 phox表达增加。此外，NF-kappaB被激活，I-kappaB α减少在胎盘从先兆子痫women.Conclusions-NADPH氧化酶是潜在的一个重要来源的ROS，可能上调NF-kappaB在先兆子痫。我们认为AT（1）-AA通过激活NADPH氧化酶参与了子痫前期ROS的产生和炎症反应。
Background-We recently identified agonistic autoantibodies directed against the angiotensin AT1 receptor (AT(1)-AA) in the plasma of preeclamptic women. To elucidate their role further, we studied the effects of AT(1)-AA on reactive oxygen species (ROS), NADPH oxidase expression, and nuclear factor-kappaB (NF-kappaB) activation.Methods and Results-We investigated human vascular smooth muscle cells (VSMC) and trophoblasts, as well as placentas. AT(1)-AA were isolated from sera of preeclamptic women. Angiotensin II (Ang II) and AT(1)-AA increased ROS production and the NADPH oxidase components, p22, p47, and p67 phox in Western blotting. We next tested if AT(1)-AA lead to NF-kappaB activation in VSMC and trophoblasts. AT(1)-AA activated NF-kappaB. Inhibitor-kappaBalpha (I-kappaBalpha) expression was reduced in response to AT(1)-AA. AT1 receptor blockade with losartan, diphenylene iodonium, tiron, and antisense against p22 phox all reduced ROS production and NF-kappaB activation. VSMC from p47phox-/- mice showed markedly reduced ROS generation and NF-kappaB activation in response to Ang II and AT(1)-AA. The p22, p47, and p67 phox expression in placentas from preeclamptic patients was increased, compared with normal placentas. Furthermore, NF-kappaB was activated and I-kappaBalpha reduced in placentas from preeclamptic women.Conclusions-NADPH oxidase is potentially an important source of ROS that may upregulate NF-kappaB in preeclampsia. We suggest that AT(1)-AA through activation of NADPH oxidase could contribute to ROS production and inflammatory responses in preeclampsia.