Continuous presence of H₂O₂ induces mitochondrial-mediated, MAPK- and caspase-independent growth inhibition and cytotoxicity in human gingival fibroblasts

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• 作者：Ji-Yeon Yu^a ; ¹ ; Seung-Youp Lee^a ; ¹ ; Young-Ok Son^b ; Xianglin Shi^b ; Soon-Sun Park^a ; Jeong-Chae Lee^a ; ^b ; ^{leejc88@jbnu.ac.kr}
• 关键词：Glucose oxidase ; Hydrogen peroxide ; Human gingival fibroblasts ; Mitochondrial stress ; ATP depletion
• 刊名：Toxicology in Vitro
• 出版年：2012
• 期刊代码：48_08872333
• 类别：pha
• 出版时间：June, 2012
• 卷：26
• 期：4
• 页码：561-570
• 文件大小：1149 K

摘要

The continuous generation of reactive oxygen species (ROS) is one of the most important events that occur during periodontal inflammation. Hydrogen peroxide (H₂O₂) is widely used in dental clinics. Many investigators have tried to elucidate the exact effect of H₂O₂ on human gingival fibroblasts (HGFs). These studies have shown that H₂O₂ induces growth inhibition and apoptosis in cells. However, the mechanisms involved in H₂O₂-induced cell death in HGFs are not completely understood. In this study, we examine how continuously generated H₂O₂ affects the viability and proliferation of HGFs using glucose oxidase (GO). We also explored the mechanisms by which the continuous presence of H₂O₂ induces cell death. GO treatment not only inhibited HGF growth and proliferation, but it also induced cell death in HGFs without typical apoptotic features such as nuclear DNA laddering. This GO-mediated cytotoxicity was proportional to the levels of intracellular ROS that were generated, rather than proportional to changes of cellular antioxidant activities. GO treatment also resulted in the loss of mitochondrial membrane potential and the relocation of mitochondrial apoptogenic factors. There was also an acute and severe depletion of cellular ATP levels. However, none of the pharmacological inhibitors specific for mitogen-activated protein kinases (MAPKs) or pancaspase prevented GO-induced cell death. Treatment with either catalase or acteoside significantly attenuated the GO-mediated cytotoxicity in the HGFs, thereby suggesting a protective effect of antioxidants against ROS-mediated gingival damage. Here we demonstrate that continuously generated H₂O₂ not only inhibits the viability and proliferation of HGFs, but also causes pyknotic/necrotic cell death through mitochondrial stress-mediated, MAPK- and caspase-independent pathways.