{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T10:53:26Z","timestamp":1790679206208,"version":"4.1.0"},"reference-count":57,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2018,5,16]],"date-time":"2018-05-16T00:00:00Z","timestamp":1526428800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>(1) Background: A high incidence of intervening sequence (IVS)4+919 G&gt;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&gt;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&gt;A genetic mutation and recapitulated several FC characteristics, including low \u03b1-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 \u03b1-galactosidase, but not \u03b1-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&gt;A mutation.<\/jats:p>","DOI":"10.3390\/ijms19051480","type":"journal-article","created":{"date-parts":[[2018,5,17]],"date-time":"2018-05-17T03:49:29Z","timestamp":1526528969000},"page":"1480","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Inhibition of Arachidonate 12\/15-Lipoxygenase Improves \u03b1-Galactosidase Efficacy in iPSC-Derived Cardiomyocytes from Fabry Patients"],"prefix":"10.3390","volume":"19","author":[{"given":"Yueh","family":"Chien","sequence":"first","affiliation":[{"name":"Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 11217, Taiwan"},{"name":"Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Jie","family":"Chou","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuh-Lih","family":"Chang","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei 11217, Taiwan"},{"name":"Department of Pharmacology, Taipei Veterans General Hospital, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin-Bang","family":"Leu","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei 11217, Taiwan"},{"name":"Heath Care and Management Center, Taipei Veterans General Hospital, Taipei 11217, Taiwan"},{"name":"Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Ping","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping-Hsing","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan"},{"name":"Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Hsiu","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuan-Hsuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Taipei Veterans General Hospital, Taipei 11217, Taiwan"},{"name":"Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Chao","family":"Chang","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, China Medical University Hospital, Taichung 40447, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Hsien","family":"Sung","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei 11217, Taiwan"},{"name":"Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Chung","family":"Yu","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei 11217, Taiwan"},{"name":"Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,5,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1093\/hmg\/3.10.1795","article-title":"Fabry disease: Twenty-three mutations including sense and antisense CPG alterations and identification of a deletional hot-spot in the \u03b1-galactosidase a gene","volume":"3","author":"Eng","year":"1994","journal-title":"Hum. 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