Research Papers:

Interleukin-18 deteriorates Fabry cardiomyopathy and contributes to the development of left ventricular hypertrophy in Fabry patients with GLA IVS4+919 G>A mutation

Yueh Chien, Chian-Shiu Chien, Huai-Chih Chiang, Wei-Lin Huang, Shih-Jie Chou, Wei-Chao Chang, Yuh-Lih Chang, Hsin-Bang Leu, Kuan-Hsuan Chen, Kang-Ling Wang, Ying-Hsiu Lai, Yung-Yang Liu, Kai-Hsi Lu, Hsin-Yang Li, Yen-Jen Sung, Yuh-Jyh Jong, Yann-Jang Chen, Chung-Hsuan Chen and Wen-Chung Yu _

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Oncotarget. 2016; 7:87161-87179. https://doi.org/10.18632/oncotarget.13552

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Yueh Chien1,7,*, Chian-Shiu Chien1,7,*, Huai-Chih Chiang1,7,*, Wei-Lin Huang1,9, Shih-Jie Chou1,7, Wei-Chao Chang4, Yuh-Lih Chang2,7, Hsin-Bang Leu3,8, Kuan-Hsuan Chen2,8, Kang-Ling Wang3,8, Ying-Hsiu Lai8, Yung-Yang Liu1,8, Kai-Hsi Lu5, Hsin-Yang Li1,9, Yen-Jen Sung9, Yuh-Jyh Jong6, Yann-Jang Chen10, Chung-Hsuan Chen11,12, Wen-Chung Yu3,13

1Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan

2Department of Pharmacy, Taipei Veterans General Hospital, Taipei, Taiwan

3Division of Cardiology & Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

4Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University and Department of Biotechnology, Asia University, Taichung, Taiwan

5Department of Medical Research, Cheng-Hsin Hospital, Taipei, Taiwan

6College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan

7Institute of Pharmacology, Taipei, Taiwan

8Institute of Clinical Medicine, Taipei, Taiwan

9Institute of Anatomy and Cell Biology, Taipei, Taiwan

10Department of Life Sciences and Institute of Genome Sciences, Taipei, Taiwan

11Genomics Research Center, Academia Sinica, Taipei, Taiwan

12Department of Chemistry, National Taiwan University, Taipei, Taiwan

13Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan

*These authors contributed equally to this work

Correspondence to:

Wen-Chung Yu, email: [email protected]

Keywords: fabry cardiomyopathy, iPSC, enzyme replacement therapy, IL-18

Received: May 11, 2016     Accepted: November 07, 2016     Published: November 24, 2016


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.

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