Pigment Epithelium-Derived Factor Mediates Autophagy and Apoptosis in Myocardial Hypoxia/Reoxygenation Injury.
Pigment Epithelium-Derived Factor Mediates Autophagy and Apoptosis in Myocardial Hypoxia/Reoxygenation Injury.
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DOI：
10.1371/journal.pone.0156059
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Hsieh CC
中科院分区：
文献类型：
--
作者：
Kuo HF;Liu PL;Chong IW;Liu YP;Chen YH;Ku PM;Li CY;Chen HH;Chiang HC;Wang CL;Chen HJ;Chen YC;Hsieh CC
色素上皮衍生因子（PEDF）是一种多功能蛋白质，具有抗血管生成、抗肿瘤、抗炎、抗氧化、抗动脉粥样硬化和心脏保护特性。虽然最近显示PEDF表达在低氧条件下被抑制，但PEDF在响应缺氧/复氧（H/R）中的功能作用仍不清楚。因此，本研究的目的是研究PEDF对心肌H/R损伤的影响。对于这些分析，利用PEDF特异性小干扰RNA表达和PEDF表达慢病毒（PEDF-LV）载体分别在体外人心肌细胞（HCM）内敲低或稳定过表达PEDF。我们注意到，活性氧（ROS）在诱导细胞死亡途径中起重要作用，包括缺血心脏的细胞凋亡和自噬。我们的研究结果表明，PEDF的过度表达导致ROS的产生和衰减的线粒体膜电位耗竭H/R条件下显着减少。此外，PEDF抑制两步凋亡途径的激活，其中半胱天冬酶依赖性（半胱天冬酶-9和半胱天冬酶-3）和半胱天冬酶非依赖性（凋亡诱导因子和核酸内切酶G），这反过来又切割几个关键底物，包括DNA修复酶聚（ADP-核糖）聚合酶。同时，PEDF的过表达也促进了自噬，这是一个通常在H/R反应中被激活的过程。因此，这些研究结果表明，PEDF通过调节抗氧化和抗凋亡因子以及促进自噬在防止H/R损伤中起关键作用。
Pigment epithelium-derived factor (PEDF) is a multifunctional protein that exhibits anti-angiogenic, antitumor, anti-inflammatory, antioxidative, anti-atherogenic, and cardioprotective properties. While it was recently shown that PEDF expression is inhibited under low oxygen conditions, the functional role of PEDF in response to hypoxia/reoxygenation (H/R) remains unclear. The goal of this study was to therefore investigate the influence of PEDF on myocardial H/R injury. For these analyses, PEDF-specific small interfering RNA-expressing and PEDF-expressing lentivirus (PEDF-LV) vectors were utilized to knockdown or stably overexpress PEDF, respectively, within human cardiomyocytes (HCM) in vitro. We noted that reactive oxygen species (ROS) play important roles in the induction of cell death pathways, including apoptosis and autophagy in ischemic hearts. Our findings demonstrate that overexpression of PEDF resulted in a significant reduction in ROS production and attenuation of mitochondrial membrane potential depletion under H/R conditions. Furthermore, PEDF inhibited the activation of a two-step apoptotic pathway in which caspase-dependent (caspase-9 and caspase-3) and caspase-independent (apoptosis inducing factor and endonuclease G), which in turn cleaves several crucial substrates including the DNA repair enzyme poly (ADP-ribose) polymerase. Meanwhile, overexpression of PEDF also promoted autophagy, a process that is typically activated in response to H/R. Therefore, these findings suggest that PEDF plays a critical role in preventing H/R injury by modulating anti-oxidant and anti-apoptotic factors and promoting autophagy.