Feng Yaling, Hu Lingqing, Xu Qian, Yuan Hua, Ba Linlin, He Yue, Che Haisha
Department of Obstetrics and Gynecology, Wuxi Maternal and Child Health Hospital Affiliated to Nanjing Medical University, Wuxi, China.
J Cardiovasc Pharmacol. 2015 Jul;66(1):96-107. doi: 10.1097/FJC.0000000000000250.
Ischemia/reperfusion (IR) injury is a critical factor in the pathogenesis of tissue injury after myocardial infarction, multiple organ failure, and other acute ischemic events. Previous studies suggest that α1-antitrypsin (AAT) plays a cytoprotective role in beta cells and human pulmonary cells. We hypothesize that AAT may have the potential to reduce IR-induced vascular injury involved in cell apoptosis and permeability. In this study, we investigate the role of AAT in human umbilical vein endothelial cells using a model wherein endothelial cell monolayers are exposed to hypoxia/reoxygenation (HR). We found that exogenous AAT alleviated HR injury in a dose- and time-dependent manner. Furthermore, by gain and loss function experiments, we demonstrated that overexpression of AAT decreased cell apoptosis and promoted proliferation by inhibiting Rac1/PAK/p38 signaling and against oxidative stress, and also reduced cellular permeability by increasing ZO-1 and occludin expression. Thus, we provided evidences to illustrate that AAT played a cytoprotective role in vascular endothelial cell under HR condition, suggesting that AAT treatment may be therapeutically beneficial to reduce IR-induced vascular injury.
缺血/再灌注（IR）损伤是心肌梗死、多器官功能衰竭及其他急性缺血事件后组织损伤发病机制中的关键因素。既往研究表明，α1-抗胰蛋白酶（AAT）在β细胞和人肺细胞中发挥细胞保护作用。我们推测，AAT可能具有减轻IR诱导的涉及细胞凋亡和通透性的血管损伤的潜力。在本研究中，我们使用内皮细胞单层暴露于缺氧/复氧（HR）的模型，研究AAT在人脐静脉内皮细胞中的作用。我们发现外源性AAT以剂量和时间依赖性方式减轻HR损伤。此外，通过功能获得和丧失实验，我们证明AAT的过表达通过抑制Rac1/PAK/p38信号传导和对抗氧化应激减少细胞凋亡并促进增殖，还通过增加ZO-1和闭合蛋白表达降低细胞通透性。因此，我们提供证据表明AAT在HR条件下对血管内皮细胞发挥细胞保护作用，提示AAT治疗可能对减轻IR诱导的血管损伤具有治疗益处。
