期刊
EMBO MOLECULAR MEDICINE
卷 7, 期 4, 页码 394-410出版社
WILEY-BLACKWELL
DOI: 10.15252/emmm.201404757
关键词
arrhythmias; atrial cardiomyocytes; atrial fibrillation; COUP-TF; ion channels
资金
- Netherlands Organization for Health Research and Development [ZonMw-TOP 40-00812-98-12086, ZonMw-MKMD-40-42600-98-036]
- Leiden University Medical Center (BW-plus) doctoral grant
- European Union [FP7-Health T2-2010-261057 'EUTRAF']
- Netherlands Heart Foundation [NHS 2008B106]
- Netherlands Organization for Scientific Research [NWO-ASPASIA 016.121.365]
- Interuniversity Attraction Poles Program [IUAP-07/07]
- European Research Council advanced grant [STEMCARDIOVASC-323182]
Drugs targeting atrial-specific ion channels, K(v)1.5 or K(ir)3.1/3.4, are being developed as new therapeutic strategies for atrial fibrillation. However, current preclinical studies carried out in non-cardiac cell lines or animal models may not accurately represent the physiology of a human cardiomyocyte (CM). In the current study, we tested whether human embryonic stem cell (hESC)-derived atrial CMs could predict atrial selectivity of pharmacological compounds. By modulating retinoic acid signaling during hESC differentiation, we generated atrial-like (hESC-atrial) and ventricular-like (hESC-ventricular) CMs. We found the expression of atrial-specific ion channel genes, KCNA5 (encoding Kv1.5) and KCNJ3 (encoding K-ir 3.1), in hESC-atrial CMs and further demonstrated that these ion channel genes are regulated by COUP-TF transcription factors. Moreover, in response to multiple ion channel blocker, vernakalant, and K(v)1.5 blocker, XEN-D0101, hESC-atrial but not hESC-ventricular CMs showed action potential (AP) prolongation due to a reduction in early repolarization. In hESC-atrial CMs, XEN-R0703, a novel K(ir)3.1/3.4 blocker restored the AP shortening caused by CCh. Neither CCh nor XEN-R0703 had an effect on hESC-ventricular CMs. In summary, we demonstrate that hESC-atrial CMs are a robust model for pre-clinical testing to assess atrial selectivity of novel antiarrhythmic drugs.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据