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- Title
Inhibition of Arachidonate 12/15-Lipoxygenase Improves α-Galactosidase Efficacy in iPSC-Derived Cardiomyocytes from Fabry Patients.
- Authors
Chien, Yueh; Chou, Shih-Jie; Chang, Yuh-Lih; Leu, Hsin-Bang; Yang, Yi-Ping; Tsai, Ping-Hsing; Lai, Ying-Hsiu; Chen, Kuan-Hsuan; Chang, Wei-Chao; Sung, Shih-Hsien; Yu, Wen-Chung
- 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.
- Subjects
CARDIOMYOPATHIES; INDUCED pluripotent stem cells; GALACTOSIDASES; ARACHIDONATE 5-lipoxygenase; BIOLOGICAL tags
- Publication
International Journal of Molecular Sciences, 2018, Vol 19, Issue 5, p1480
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms19051480