Impaired vitamin D signaling causes LMNA mutation-related cardiomyopathy

Mutations of the lamin A/C gene (LMNA) cause a variety of diseases including dilated cardiomyopathy (DCM). LMNA-related DCM often leads to severe heart failure, but the underlying pathophysiology is unknown. Here we show that vitamin D receptor (VDR) signaling is critically involved in LMNA-related DCM. We established iPS cells from DCM patients with an LMNA mutation and found that the iPS cell-derived cardiomyocytes (iPSCMs) showed remarkable DNA damage and reduced contractility compared with the isogenic control. Screening of a chemical library revealed that vitamin D2 reduced DNA damage of the mutant iPSCMs. RNA sequencing analysis showed that expression levels of putative downstream genes of VDR including DNA repair factors were downregulated in the mutant iPSCMs, which were upregulated by vitamin D2. Protein-protein interaction screening revealed that the binding of VDR to mutant LMNA was more robust than to wild-type LMNA, resulting in attenuated VDR signaling in the mutant iPSCMs. Vitamin D2 administration reduced DNA damage and improved cardiac function in pressure overload-induced heart failure mice. These results indicate that impaired DNA repair caused by reduced transcriptional activity of VDR induces cardiac dysfunction of LMNA-related DCM and suggest that VDR signaling is a potential therapeutic target for patients with DCM and heart failure.