Department of Pharmacy, University of Salerno. Via Giovanni Paolo II, Fisciano, Salerno, Italy.
Department of Pharmacy, University of Salerno. Via Giovanni Paolo II, Fisciano, Salerno, Italy.
Toxicol In Vitro. 2018 Mar;47:120-128. doi: 10.1016/j.tiv.2017.11.004. Epub 2017 Nov 16.
Hypoxia is the basis of many myocardial conditions, and it can initiate cell death programs, among which apoptosis is well-known. Connexin 43 (Cx43), the major component of cardiomyocyte Gap Junctions, is important in cardioprotection. Cx43is involved in ischemia/reperfusion injury and ischemic preconditioning's protection in vitro; however, its role on cardiomyocyte under hypoxia is still unclear. Reports have shown that Cx43 is also located at the inner membrane of mitochondria where it has been implicated in enhanced ischemic preconditioning response. In this study, to evaluate the role of mitochondrial Cx43 in hypoxia, we used an in vitro model of chemical hypoxia induced by Cobalt chloride (CoCl) in H9c2 cell line. CoCl (50-100-150μM) was administered for 3 or 6h, alone or combined with Radicicol, that inhibits Cx43 translocation on mitochondria, to demonstrate the crucial role of mitochondrial Cx43 in the cardioprotection. In fact, reduction of Cx43 translocation on mitochondria increases mitochondrial ROS production, cytosolic and mitochondrial calcium overload and mitochondrial membrane depolarization, thus resulting in an increase of the triggering apoptotic pathway. In conclusion, our study demonstrates the involvement of mitochondrial Cx43 in the apoptotic process in a chemical hypoxia model and suggests that mitochondrial Cx43 plays a crucial role in cytoprotection.
缺氧是许多心肌疾病的基础，可以启动细胞死亡程序，其中细胞凋亡是众所周知的。间隙连接蛋白 43（Cx43）是心肌细胞缝隙连接的主要组成部分，在心脏保护中很重要。Cx43 参与体外缺血/再灌注损伤和缺血预处理的保护；然而，其在缺氧状态下对心肌细胞的作用尚不清楚。有报道称，Cx43 也位于线粒体的内膜上，它与增强的缺血预处理反应有关。在这项研究中，为了评估线粒体 Cx43 在缺氧中的作用，我们使用了化学缺氧的体外模型，由氯化钴（CoCl）在 H9c2 细胞系中诱导。CoCl（50-100-150μM）单独或与抑制 Cx43 在线粒体易位的 Radicicol 联合给药 3 或 6 小时，以证明线粒体 Cx43 在心脏保护中的关键作用。事实上，减少线粒体 Cx43 的易位会增加线粒体 ROS 的产生、胞质和线粒体钙超载以及线粒体膜去极化，从而导致触发凋亡途径的增加。总之，我们的研究表明，线粒体 Cx43 参与了化学缺氧模型中的凋亡过程，并表明线粒体 Cx43 在细胞保护中起着至关重要的作用。
