Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE

Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.

Mutation* ; Signal Transduction*; Cardiomyopathy, Dilated/*genetics ; Lamin Type A/*genetics ; Platelet-Derived Growth Factor/*metabolism ; Receptor, Platelet-Derived Growth Factor beta/*metabolism; Arrhythmias, Cardiac/metabolism ; Arrhythmias, Cardiac/pathology ; Calcium/metabolism ; Cells, Cultured ; Chromatin/chemistry ; Chromatin/genetics ; Chromatin/metabolism ; Chromatin Assembly and Disassembly/genetics ; Haploinsufficiency/genetics ; Homeostasis ; Humans ; In Vitro Techniques ; Induced Pluripotent Stem Cells/pathology ; Models, Biological ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology ; Nonsense Mediated mRNA Decay ; RNA, Messenger/analysis ; RNA, Messenger/genetics ; Single-Cell Analysis

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-β (PDGFRB) as a potential therapeutic target.

Comment in: Nat Rev Cardiol. 2019 Oct;16(10):579. (PMID: 31371813)

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0 (Chromatin)
0 (LMNA protein, human)
0 (Lamin Type A)
0 (Platelet-Derived Growth Factor)
0 (RNA, Messenger)
0 (lamin C)
EC 2.7.10.1 (Receptor, Platelet-Derived Growth Factor beta)
SY7Q814VUP (Calcium)

Date Created: 20190719 Date Completed: 20191210 Latest Revision: 20240421

20240421

PMC6779479

10.1038/s41586-019-1406-x

31316208