標題: | Interleukin-18 deteriorates Fabry cardiomyopathy and contributes to the development of left ventricular hypertrophy in Fabry patients with GLA IVS4+919 G>A mutation |
作者: | Chien, Yueh Chien, Chian-Shiu Chiang, Huai-Chih Huang, Wei-Lin Chou, Shih-Jie Chang, Wei-Chao Chang, Yuh-Lih Leu, Hsin-Bang Chen, Kuan-Hsuan Wang, Kang-Ling Lai, Ying-Hsiu Liu, Yung-Yang Lu, Kai-Hsi Li, Hsin-Yang Sung, Yen-Jen Jong, Yuh-Jyh Chen, Yann-Jang Chen, Chung-Hsuan Yu, Wen-Chung 生物科技學院 College of Biological Science and Technology |
關鍵字: | Fabry cardiomyopathy;iPSC;enzyme replacement therapy;IL-18 |
公開日期: | 27-十二月-2016 |
摘要: | 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 a-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. |
URI: | http://dx.doi.org/10.18632/oncotarget.13552 http://hdl.handle.net/11536/133075 |
ISSN: | 1949-2553 |
DOI: | 10.18632/oncotarget.13552 |
期刊: | ONCOTARGET |
Volume: | 7 |
Issue: | 52 |
起始頁: | 87161 |
結束頁: | 87179 |
顯示於類別: | 期刊論文 |