Adenoviral Gene Transfer of Hepatic Stimulator Substance Confers Resistance Against Hepatic Ischemia-Reperfusion Injury by Improving Mitochondrial Function
Adenoviral Gene Transfer of Hepatic Stimulator Substance Confers Resistance Against Hepatic Ischemia-Reperfusion Injury by Improving Mitochondrial Function
复制标题
肝脏刺激物质的腺病毒基因转移通过改善线粒体功能来抵抗肝脏缺血再灌注损伤
DOI：
10.1089/hum.2012.219
复制
发表时间：
2013-04-01
影响因子：
4.2
通讯作者：
An, Wei
中科院分区：
文献类型：
--
作者：
Jiang, Shu-Jun;Li, Wen;An, Wei
肝刺激物质(HSS)被认为可以保护肝细胞免受各种毒素的伤害。然而，HSS在肝脏缺血再灌注(I/R)损伤中的确切作用尚不清楚。本研究旨在阐明HSS过表达是否能减轻肝脏缺血再灌注损伤及其可能的机制。采用小鼠在体肝I/R损伤模型和体外缺氧-复氧(H/R)细胞模型评价HSS对腺病毒基因转移后HSS的保护作用。此外，还探讨了线粒体对HSS保护的可能机制。有效地将HSS基因转移到肝脏可以抑制小鼠的肝脏I/R损伤，这体现在肝功能测试的改善、肝脏形态的保存和肝细胞凋亡的减少。HSS过表达还能抑制H/R诱导的细胞死亡，细胞存活率和细胞凋亡率检测结果显示。其作用机制可能与保护线粒体超微结构、保护线粒体膜电位、抑制细胞色素c渗漏和抑制caspase活性有关，从而减轻线粒体功能障碍和线粒体依赖性细胞凋亡。此外，抑制H/R诱导的线粒体ROS生成和维持线粒体呼吸链复合体活性可能参与了这一机制。这一新的功能拓展了HSS在临床上应用于肝切除、肝移植等I/R损伤预防的可能性。
Hepatic stimulator substance (HSS) has been suggested to protect liver cells from various toxins. However, the precise role of HSS in hepatic ischemia-reperfusion (I/R) injury remains unknown. This study aims to elucidate whether overexpression of HSS could attenuate hepatic ischemia-reperfusion injury and its possible mechanisms. Both in vivo hepatic I/R injury in mice and in vitro hypoxia-reoxygenation (H/R) in a cell model were used to evaluate the effect of HSS protection after adenoviral gene transfer. Moreover, a possible mitochondrial mechanism of HSS protection was investigated. Efficient transfer of the HSS gene into liver inhibited hepatic I/R injury in mice, as evidenced by improvement in liver function tests, the preservation of hepatic morphology, and a reduction in hepatocyte apoptosis. HSS overexpression also inhibited H/R-induced cell death, as detected by cell viability and cell apoptosis assays. The underlying mechanism of this hepatic protection might involve the attenuation of mitochondrial dysfunction and mitochondrial-dependent cell apoptosis, as shown by the good preservation of mitochondrial ultrastructure, mitochondrial membrane potential, and the inhibition of cytochrome c leakage and caspase activity. Moreover, the suppression of H/R-induced mitochondrial ROS production and the maintenance of mitochondrial respiratory chain complex activities may participate in this mechanism. This new function of HSS expands the possibility of its application for the prevention of I/R injury, such as hepatic resection and liver transplantation in clinical practice.