Interleukin-18 deteriorates Fabry cardiomyopathy and contributes to the development of left ventricular hypertrophy in Fabry patients with GLA IVS4+919 G>A mutation
| Autor: | Chung-Hsuan Chen, Yuh Lih Chang, Ying Hsiu Lai, Yann Jang Chen, Yen Jen Sung, Wei Lin Huang, Huai Chih Chiang, Kuan Hsuan Chen, Wei Chao Chang, Wen Chung Yu, Hsin Bang Leu, Yuh Jyh Jong, Shih Jie Chou, Hsin Yang Li, Chian Shiu Chien, Yueh Chien, Kai Hsi Lu, Kang Ling Wang, Yung Yang Liu |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Gerontology Oncology medicine.medical_specialty Induced Pluripotent Stem Cells Globotriaosylceramide Cardiomyopathy Disease Left ventricular hypertrophy 03 medical and health sciences chemistry.chemical_compound Internal medicine medicine Humans Enzyme Replacement Therapy Myocytes Cardiac iPSC business.industry Interleukin-18 Enzyme replacement therapy Middle Aged medicine.disease Molecular medicine Fabry disease 030104 developmental biology chemistry alpha-Galactosidase Heart failure Mutation Fabry Disease Female Hypertrophy Left Ventricular fabry cardiomyopathy business IL-18 Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.13552 |
| Popis: | // Yueh Chien 1, 7, * , Chian-Shiu Chien 1, 7, * , Huai-Chih Chiang 1, 7, * , Wei-Lin Huang 1, 9 , Shih-Jie Chou 1, 7 , Wei-Chao Chang 4 , Yuh-Lih Chang 2, 7 , Hsin-Bang Leu 3, 8 , Kuan-Hsuan Chen 2, 8 , Kang-Ling Wang 3, 8 , Ying-Hsiu Lai 8 , Yung-Yang Liu 1, 8 , Kai-Hsi Lu 5 , Hsin-Yang Li 1, 9 , Yen-Jen Sung 9 , Yuh-Jyh Jong 6 , Yann-Jang Chen 10 , Chung-Hsuan Chen 11, 12 , Wen-Chung Yu 3, 13 1 Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan 2 Department of Pharmacy, Taipei Veterans General Hospital, Taipei, Taiwan 3 Division of Cardiology & Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 4 Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University and Department of Biotechnology, Asia University, Taichung, Taiwan 5 Department of Medical Research, Cheng-Hsin Hospital, Taipei, Taiwan 6 College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan 7 Institute of Pharmacology, Taipei, Taiwan 8 Institute of Clinical Medicine, Taipei, Taiwan 9 Institute of Anatomy and Cell Biology, Taipei, Taiwan 10 Department of Life Sciences and Institute of Genome Sciences, Taipei, Taiwan 11 Genomics Research Center, Academia Sinica, Taipei, Taiwan 12 Department of Chemistry, National Taiwan University, Taipei, Taiwan 13 Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan * These authors contributed equally to this work Correspondence to: Wen-Chung Yu, email: wcyu@vghtpe.gov.tw Keywords: fabry cardiomyopathy, iPSC, enzyme replacement therapy, IL-18 Received: May 11, 2016 Accepted: November 07, 2016 Published: November 24, 2016 ABSTRACT Rationale: A high incidence of GLA IVS4+919 G>A mutation in patients with Fabry disease of the later-onset cardiac phenotype, has been reported in Taiwan. However, suitable biomarkers or potential therapeutic surrogates for Fabry cardiomyopathy (FC) in such patients under enzyme replacement treatment (ERT) remain unknown. Objective: Using FC patients carrying IVS4+919 G>A mutation, we constructed an induced pluripotent stem cell (iPSC)-based disease model to investigate the pathogenetic biomarkers and potential therapeutic targets in ERT-treated FC. Results and methods: The iPSC-differentiated cardiomyocytes derived from FC-patients (FC-iPSC-CMs) carried IVS4+919 G>A mutation recapitulating FC characteristics, including low α-galactosidase A enzyme activity, cellular hypertrophy, and massive globotriaosylceramide accumulation. Microarray analysis revealed that interleukin-18 (IL-18), a pleiotropic cytokine involved in various myocardial diseases, was the most highly upregulated marker in FC-iPSC-CMs. Meanwhile, IL-18 levels were found to be significantly elevated in the culture media of FC-iPSC-CMs and patients’ sera. Notably, the serum IL-18 levels were highly paralleled with the progression of left ventricular hypertrophy in Fabry patients receiving ERT. Finally, using FC-iPSC-CMs as in vitro FC model, neutralization of IL-18 with specific antibodies combined with ERT synergistically reduced the secretion of IL-18 and the progression of cardiomyocyte hypertrophy in FC-iPSC-CMs. Conclusion: Our data demonstrated that cardiac IL-18 and circulating IL-18 are involved in the pathogenesis of FC and LVH. IL-18 may be a novel marker for evaluating ERT efficacy, and targeting IL-18 might be a potential adjunctive therapy combined with ERT for the treatment of advanced cardiomyopathy in FC patients with IVS4+919 G>A mutation. |
| Databáze: | OpenAIRE |
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