Inhibition of arachidonate 12/15-lipoxygenase improves α-galactosidase efficacy in iPSC-derived cardiomyocytes from fabry patients

Yueh Chien, Shih Jie Chou, Yuh Lih Chang, Hsin Bang Leu, Yi Ping Yang, Ping Hsing Tsai, Ying Hsiu Lai, Kuan Hsuan Chen, Wei Chao Chang, Shih Hsien Sung, Wen Chung Yu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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.

Original languageEnglish
Article number1480
JournalInternational Journal Of Molecular Sciences
Volume19
Issue number5
DOIs
StatePublished - 16 May 2018

Keywords

  • Alox12/15
  • Enzyme replacement therapy
  • Fabry cardiomyopathy
  • IPSC

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