title: Imbalanced Production of Reactive Oxygen Species and Mitochondrial Antioxidant SOD2 in Fabry Disease-Specific Human Induced Pluripotent Stem Cell-Differentiated Vascular Endothelial Cells.
abstract: Fabry disease (FD) is an X-linked inherited lysosomal storage disease caused by α-galactosidase A (GLA) deficiency. Progressive intracellular accumulation of globotriaosylceramide (Gb3) is considered to be pathogenically responsible for the phenotype variability of FD that causes cardiovascular dysfunction; however, molecular mechanisms underlying the impairment of FD-associated cardiovascular tissues remain unclear. In this study, we reprogrammed human induced pluripotent stem cells (hiPSCs) from peripheral blood cells of patients with FD (FD-iPSCs); subsequently differentiated them into vascular endothelial-like cells (FD-ECs) expressing CD31, VE-cadherin, and vWF; and investigated their ability to form vascular tube-like structures. FD-ECs recapitulated the FD pathophysiological phenotype exhibiting intracellular Gb3 accumulation under a transmission electron microscope. Moreover, compared with healthy control iPSC-derived endothelial cells (NC-ECs), reactive oxygen species (ROS) production considerably increased in FD-ECs. Microarray analysis was performed to explore the possible mechanism underlying Gb3 accumulation-induced ROS production in FD-ECs. Our results revealed that superoxide dismutase 2 (SOD2), a mitochondrial antioxidant, was significantly downregulated in FD-ECs. Compared with NC-ECs, AMPK activity was significantly enhanced in FD-ECs. Furthermore, to investigate the role of Gb3 in these effects, human umbilical vein endothelial cells (HUVECs) were treated with Gb3. After Gb3 treatment, we observed that SOD2 expression was suppressed and AMPK activity was enhanced in a dose-dependent manner. Collectively, our results indicate that excess accumulation of Gb3 suppressed SOD2 expression, increased ROS production, enhanced AMPK activation, and finally caused vascular endothelial dysfunction. Our findings suggest that dysregulated mitochondrial ROS may be a potential target for treating FD.
authors.forename: Wei-Lien
authors.initials: WL
authors.lastname: Tseng
authors.forename: Shih-Jie
authors.initials: SJ
authors.lastname: Chou
authors.forename: Huai-Chih
authors.initials: HC
authors.lastname: Chiang
authors.forename: Mong-Lien
authors.initials: ML
authors.lastname: Wang
authors.forename: Chian-Shiu
authors.initials: CS
authors.lastname: Chien
authors.forename: Kuan-Hsuan
authors.initials: KH
authors.lastname: Chen
authors.forename: Hsin-Bang
authors.initials: HB
authors.lastname: Leu
authors.forename: Chien-Ying
authors.initials: CY
authors.lastname: Wang
authors.forename: Yuh-Lih
authors.initials: YL
authors.lastname: Chang
authors.forename: Yung-Yang
authors.initials: YY
authors.lastname: Liu
authors.forename: Yuh-Jyh
authors.initials: YJ
authors.lastname: Jong
authors.forename: Shinn-Zong
authors.initials: SZ
authors.lastname: Lin
authors.forename: Shih-Hwa
authors.initials: SH
authors.lastname: Chiou
authors.forename: Shing-Jong
authors.initials: SJ
authors.lastname: Lin
authors.forename: Wen-Chung
authors.initials: WC
authors.lastname: Yu
mesh_terms: D000975:Antioxidants / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D000795:Fabry Disease / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2