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RSS FeedsIJMS, Vol. 19, Pages 1480: Inhibition of Arachidonate 12/15-Lipoxygenase Improves ?-Galactosidase Efficacy in iPSC-Derived Cardiomyocytes from Fabry Patients (International Journal of Molecular Sciences)

 
 

20 may 2018 18:03:15

 
IJMS, Vol. 19, Pages 1480: Inhibition of Arachidonate 12/15-Lipoxygenase Improves ?-Galactosidase Efficacy in iPSC-Derived Cardiomyocytes from Fabry Patients (International Journal of Molecular Sciences)
 


(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 ?-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 ?-galactosidase, but not ?-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.


 
66 viewsCategory: Biochemistry, Biophysics, Molecular Biology
 
IJMS, Vol. 19, Pages 1481: Exploration of ABA Responsive miRNAs Reveals a New Hormone Signaling Crosstalk Pathway Regulating Root Growth of Populus euphratica (International Journal of Molecular Sciences)
IJMS, Vol. 19, Pages 1482: Synthesis, Molecular Structure, Anticancer Activity, and QSAR Study of N-(aryl/heteroaryl)-4-(1H-pyrrol-1-yl)Benzenesulfonamide Derivatives (International Journal of Molecular Sciences)
 
 
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