Research ArticleCARDIOMYOPATHY

Clinical trial in a dish using iPSCs shows lovastatin improves endothelial dysfunction and cellular cross-talk in LMNA cardiomyopathy

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Science Translational Medicine  29 Jul 2020:
Vol. 12, Issue 554, eaax9276
DOI: 10.1126/scitranslmed.aax9276

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Lovastatin for cardiolaminopathy

Mutations in LMNA, which encodes nuclear envelope proteins, can cause dilated cardiomyopathy and vascular endothelial dysfunction. To understand mechanisms contributing to this disease, Sayed et al. studied induced pluripotent stem cell–derived endothelial cells (iPSC-ECs) from a family harboring an LMNA mutation. They found down-regulation of KLF2, a protein involved in mechanotransduction, which caused endothelial dysfunction. Lovastatin could induce KLF2 in iPSC-ECs, improving cardiomyocyte function in coculture and clinical EC function in two patients treated with the drug. This study demonstrates a workflow for identifying and validating potential drug treatments for patients with cardiolaminopathy.

Abstract

Mutations in LMNA, the gene that encodes lamin A and C, causes LMNA-related dilated cardiomyopathy (DCM) or cardiolaminopathy. LMNA is expressed in endothelial cells (ECs); however, little is known about the EC-specific phenotype of LMNA-related DCM. Here, we studied a family affected by DCM due to a frameshift variant in LMNA. Human induced pluripotent stem cell (iPSC)–derived ECs were generated from patients with LMNA-related DCM and phenotypically characterized. Patients with LMNA-related DCM exhibited clinical endothelial dysfunction, and their iPSC-ECs showed decreased functionality as seen by impaired angiogenesis and nitric oxide (NO) production. Moreover, genome-edited isogenic iPSC lines recapitulated the EC disease phenotype in which LMNA-corrected iPSC-ECs showed restoration of EC function. Simultaneous profiling of chromatin accessibility and gene expression dynamics by combining assay for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA sequencing (RNA-seq) as well as loss-of-function studies identified Krüppel-like factor 2 (KLF2) as a potential transcription factor responsible for the EC dysfunction. Gain-of-function studies showed that treatment of LMNA iPSC-ECs with KLF2 agonists, including lovastatin, rescued the EC dysfunction. Patients with LMNA-related DCM treated with lovastatin showed improvements in clinical endothelial dysfunction as indicated by increased reactive hyperemia index. Furthermore, iPSC-derived cardiomyocytes (iPSC-CMs) from patients exhibiting the DCM phenotype showed improvement in CM function when cocultured with iPSC-ECs and lovastatin. These results suggest that impaired cross-talk between ECs and CMs can contribute to the pathogenesis of LMNA-related DCM, and statin may be an effective therapy for vascular dysfunction in patients with cardiolaminopathy.

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