血管紧张素II(AngII)是肾素-血管紧张素系统(RAS)的主要效应肽,并通过对一系列不同细胞类型的影响来促进心血管疾病的发病机理,包括中枢神经元。AngII神经元内信号是介导的,至少在某种程度上,通过活性氧,特别是超氧化物(O2(•-))。最近,已经发现线粒体是AngII诱导的O2(·-)的主要亚细胞来源。我们以前报道过锰超氧化物歧化酶(MnSOD)的过表达,线粒体基质定位的O2(•-)清除酶,抑制AngII神经元内信号传导。有趣的是,铜/锌超氧化物歧化酶(CuZnSOD)的过表达,被认为主要位于细胞质中,类似地抑制AngII神经元内信号传导,并提供针对AngII介导的神经源性高血压的保护作用.在这里,我们检验了这样的假设:在中枢神经元中CuZnSOD过表达定位于线粒体并通过清除线粒体O2(•-)来抑制AngII神经元内信号传导。使用神经元细胞培养模型(CATH。a神经元),我们证明内源性和腺病毒介导的过表达CuZnSOD(AdCuZnSOD)都存在于线粒体中。此外,我们显示CuZnSOD的过表达减弱了AngII介导的线粒体O2(•-)水平的增加和AngII诱导的神经元钾电流的抑制。一起来看,这些数据清楚地表明,神经元中过表达的CuZnSOD位于线粒体,清除AngII诱导的线粒体O2(•-),并抑制AngII神经元内信号传导。
Angiotensin II (AngII) is the main effector peptide of the renin-angiotensin system (RAS), and contributes to the pathogenesis of cardiovascular disease by exerting its effects on an array of different cell types, including central neurons. AngII intra-neuronal signaling is mediated, at least in part, by reactive oxygen species, particularly superoxide (O2 (•-)). Recently, it has been discovered that mitochondria are a major subcellular source of AngII-induced O2 (•-). We have previously reported that over-expression of manganese superoxide dismutase (MnSOD), a mitochondrial matrix-localized O2 (•-) scavenging enzyme, inhibits AngII intra-neuronal signaling. Interestingly, over-expression of copper/zinc superoxide dismutase (CuZnSOD), which is believed to be primarily localized to the cytoplasm, similarly inhibits AngII intra-neuronal signaling and provides protection against AngII-mediated neurogenic hypertension. Herein, we tested the hypothesis that CuZnSOD over-expression in central neurons localizes to mitochondria and inhibits AngII intra-neuronal signaling by scavenging mitochondrial O2 (•-). Using a neuronal cell culture model (CATH.a neurons), we demonstrate that both endogenous and adenovirus-mediated over-expressed CuZnSOD (AdCuZnSOD) are present in mitochondria. Furthermore, we show that over-expression of CuZnSOD attenuates the AngII-mediated increase in mitochondrial O2 (•-) levels and the AngII-induced inhibition of neuronal potassium current. Taken together, these data clearly show that over-expressed CuZnSOD in neurons localizes in mitochondria, scavenges AngII-induced mitochondrial O2 (•-), and inhibits AngII intra-neuronal signaling.