期刊
NATURE
卷 572, 期 7769, 页码 335-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-019-1406-x
关键词
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资金
- AHA [17MERIT33610009, 17IRG33410532]
- NIH [R01 HL128170, R01 HL113006, R01 HL130020, R01 HL132875, R01 HL141851, K99 HL133473, F32 HL139045, P50 HG007735]
- Leducq Foundation [18CVD05]
- Prince Mahidol Award Foundation
- German Research Foundation
- National Research Foundation of Korea [2012R1A5A2A28671860, 2019R1C1C1010675]
- CIRM [GC1R-06673-A, R24 HL117756]
- Howard Hughes Medical Institute
- [R01 HL139679]
- [R00 HL104002]
- National Research Foundation of Korea [2019R1C1C1010675] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Lamin A/C (LMNA) is one of the most frequently mutated genes associated with dilated cardiomyopathy (DCM). DCM related to mutations in LMNA is a common inherited cardiomyopathy that is associated with systolic dysfunction and cardiac arrhythmias. Here we modelled the LMNA-related DCM in vitro using patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Electrophysiological studies showed that the mutant iPSC-CMs displayed aberrant calcium homeostasis that led to arrhythmias at the single-cell level. Mechanistically, we show that the platelet-derived growth factor (PDGF) signalling pathway is activated in mutant iPSC-CMs compared to isogenic control iPSC-CMs. Conversely, pharmacological and molecular inhibition of the PDGF signalling pathway ameliorated the arrhythmic phenotypes of mutant iPSC-CMs in vitro. Taken together, our findings suggest that the activation of the PDGF pathway contributes to the pathogenesis of LMNA-related DCM and point to PDGF receptor-beta (PDGFRB) as a potential therapeutic target.
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