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