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Int. J. Mol. Sci. 2018, 19(5), 1480; https://doi.org/10.3390/ijms19051480

Inhibition of Arachidonate 12/15-Lipoxygenase Improves α-Galactosidase Efficacy in iPSC-Derived Cardiomyocytes from Fabry Patients

1
Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 11217, Taiwan
2
Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan
3
Department of Pharmacology, Taipei Veterans General Hospital, Taipei 11217, Taiwan
4
Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei 11217, Taiwan
5
Heath Care and Management Center, Taipei Veterans General Hospital, Taipei 11217, Taiwan
6
Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan
7
Center for Molecular Medicine, China Medical University Hospital, Taichung 40447, Taiwan
*
Author to whom correspondence should be addressed.
Received: 21 March 2018 / Revised: 3 May 2018 / Accepted: 8 May 2018 / Published: 16 May 2018
(This article belongs to the Special Issue Disease Modeling Using Human Induced Pluripotent Stem Cells)
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Abstract

(1) Background: A high incidence of intervening sequence (IVS)4+919 G>A mutation with later-onset cardiac phenotype have been reported in a majority of Taiwan Fabry cohorts. Some evidence indicated that conventional biomarkers failed to predict the long-term progression and therapeutic outcome; (2) Methods: In this study, we constructed an induced pluripotent stem cell (iPSC)-based platform from Fabry cardiomyopathy (FC) patients carrying IVS4+919 G>A mutation to screen for potential targets that may help the conventional treatment; (3) Results: The FC-patient-derived iPSC-differentiated cardiomyocytes (FC-iPSC-CMs) carried an expected IVS4+919 G>A genetic mutation and recapitulated several FC characteristics, including low α-galactosidase A enzyme activity and cellular hypertrophy. The proteomic analysis revealed that arachidonate 12/15-lipoxygenase (Alox12/15) was the most highly upregulated marker in FC-iPSC-CMs, and the metabolites of Alox12/15, 12(S)- and 15(S)-hydroxyeicosatetraenoic acid (HETE), were also elevated in the culture media. Late administration of Alox12/15 pharmacological inhibitor LOXBlock-1 combined with α-galactosidase, but not α-galactosidase alone, effectively reduced cardiomyocyte hypertrophy, the secretion of 12(S)- and 15(S)-HETE and the upregulation of fibrotic markers at the late phase of FC; (4) Conclusions: Our study demonstrates that cardiac Alox12/15 and circulating 12(S)-HETE/15(S)-HETE are involved in the pathogenesis of FC with IVS4+919 G>A mutation. View Full-Text
Keywords: Fabry cardiomyopathy; iPSC; enzyme replacement therapy; Alox12/15 Fabry cardiomyopathy; iPSC; enzyme replacement therapy; Alox12/15
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Chien, Y.; Chou, S.-J.; Chang, Y.-L.; Leu, H.-B.; Yang, Y.-P.; Tsai, P.-H.; Lai, Y.-H.; Chen, K.-H.; Chang, W.-C.; Sung, S.-H.; Yu, W.-C. Inhibition of Arachidonate 12/15-Lipoxygenase Improves α-Galactosidase Efficacy in iPSC-Derived Cardiomyocytes from Fabry Patients. Int. J. Mol. Sci. 2018, 19, 1480.

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