Imbalanced Production of Reactive Oxygen Species and Mitochondrial Antioxidant SOD2 in Fabry Disease-Specific Human Induced Pluripotent Stem Cell-Differentiated Vascular Endothelial Cells

Wei Lien Tseng, Shih Jie Chou, Huai Chih Chiang, Mong Lien Wang, Chian Shiu Chien, Kuan Hsuan Chen, Hsin-Bang Leu, Chien Ying Wang, Yuh Lih Chang, Yung Yang Liu, Yuh-Jyh Jong, Shinn-Zong Lin, Shih-Hwa Chiou, Shing-Jong Lin, Wen-Chung Yu

Research output: Contribution to journalLetterpeer-review

15 Scopus citations

Abstract

Fabry disease (FD) is an X-linked inherited lysosomal storage disease caused by alpha-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-likecells (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.
Original languageEnglish
Pages (from-to)513-527
Number of pages15
JournalCell Transplantation
Volume26
Issue number3
DOIs
StatePublished - 2017

Keywords

  • Fabry disease (FD); Vascular endothelial dysfunction; Superoxide dismutase 2 (SOD2); Gb3 accumulation; Induced pluripotent stem cells (iPSCs)
  • ACTIVATED PROTEIN-KINASE; MANGANESE SUPEROXIDE-DISMUTASE; OXIDATIVE STRESS; ALPHA-GALACTOSIDASE; DILATED CARDIOMYOPATHY; REPLACEMENT THERAPY; NEONATAL LETHALITY; MNSOD DEFICIENCY; MICE; GLOBOTRIAOSYLCERAMIDE

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