Hyperuricemia induces endothelial dysfunction via mitochondrial Na+/Ca2+ exchanger-mediated mitochondrial calcium overload
Hyperuricemia induces endothelial dysfunction via mitochondrial Na+/Ca2+ exchanger-mediated mitochondrial calcium overload
复制标题
DOI：
10.1016/j.ceca.2012.01.003
复制
发表时间：
2012-05-01
期刊：
影响因子：
4
通讯作者：
Wu Di
中科院分区：
文献类型：
--
作者：
Hong Quan;Qi Ka;Wu Di
背景：尿酸（UA）已被证明是内皮功能障碍的致病因子，其中ROS的产生起着重要作用。线粒体内钙超载可促进ROS的产生。我们假设，线粒体中的钙转导有助于UA诱导的内皮功能障碍。方法和结果：我们首先证明，高浓度的UA引起内皮功能障碍，标志着eNOS蛋白表达和NO释放在体外减少。我们进一步发现，高浓度的UA增加了[Ca 2 +]（mito），总细胞内ROS，H2 O2和线粒体O-2（中心点-）的水平，和Δ psi（mito），但不是[Ca 2 +]（cyt）水平。当线粒体钙通道NCXmito和MCU分别被CGP-37157和Ru 360阻断时，UA诱导的[Ca 2 +]（mito）和总细胞内ROS水平的增加显著降低。通过抑制NCXmito而不是MCU，O-2（中心点-）和Delta psi（mito）的线粒体水平降低。此外，抑制NCXmito，但不是MCU，阻止UA诱导的eNOS蛋白表达和NO releasing.Conclusions的减少：高浓度的UA诱导的线粒体O-2（中心点-）的产生增加是由线粒体钙超载触发，并最终导致内皮功能障碍。在这个过程中，NCXmito的激活是钙流入线粒体的主要原因。我们的研究结果为UA诱导的内皮功能障碍提供了一个新的病理生理机制，并可能为临床医生提供一个新的治疗靶点。(C)2012爱思唯尔有限公司保留所有权利。
Background: Uric acid (UA) has proven to be a causal agent in endothelial dysfunction in which ROS production plays an important role. Calcium overload in mitochondria can promote the mitochondrial production of ROS. We hypothesize that calcium transduction in mitochondria contributes to UA-induced endothelial dysfunction.Methods and results: We first demonstrated that high concentrations of UA cause endothelial dysfunction, marked by a reduction in eNOS protein expression and NO release in vitro. We further found that a high concentration of UA increased levels of [Ca2+](mito), total intracellular ROS, H2O2, and mitochondrial O-2(center dot-), and Delta psi(mito) but not the [Ca2+](cyt) level. When the mitochondrial calcium channels NCXmito and MCU were blocked by CGP-37157 and Ru360, respectively, the UA-induced increases in the levels of [Ca2+](mito) and total intracellular ROS were significantly reduced. Mitochondrial levels of O-2(center dot-) and Delta psi(mito) were reduced by inhibition of NCXmito but not of MCU. Moreover, inhibition of NCXmito, but not of MCU, blocked the UA-induced reductions in eNOS protein expression and NO release.Conclusions: The increased generation of mitochondrial O-2(center dot-) induced by a high concentration of UA is triggered by mitochondrial calcium overload and ultimately leads to endothelial dysfunction. In this process, the activation of NCXmito is the major cause of the influx of calcium into mitochondria. Our results provide a new pathophysiological mechanism for UA-induced endothelial dysfunction and may offer a new therapeutic target for clinicians. (C) 2012 Elsevier Ltd. All rights reserved.