Activation of PDGF Pathway Links LMNA Mutation to Dilated Cardiomyopathy

Lamin A/C (LMNA) is one of the most frequently mutated genes in dilated cardiomyopathy (DCM). LMNA-related DCM is a common inherited cardiomyopathy associated with systolic dysfunction and high prevalence arrhythmias. Here we modeled the LMNA-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 leading to arrhythmias at the single-cell level. Mechanistically, we uncovered that the platelet-derived growth factor (PDGF) signaling pathway was activated in mutant iPSC-CMs when compared to isogenic controls. Conversely, pharmacological and molecular inhibition of the PDGF signaling pathway ameliorated the arrhythmia phenotypes of mutant iPSC-CMs in vitro. Taken together, our findings suggest that the activation of the PDGF pathway contributes to the pathogenesis of the LMNA-DCM and point to PDGF receptor beta (PDGFRB) as a potential therapeutic target.