Clinical trial in a dish using iPSCs shows lovastatin improves endothelial dysfunction and cellular cross-talk in LMNA cardiomyopathy
- 29 July 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 12 (554)
- https://doi.org/10.1126/scitranslmed.aax9276
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.Keywords
Funding Information
- National Institutes of Health (R01 HL130020, R01 HL113006, R01 HL123968, R01 HL141371, R01 HL141851, and R01 HL126527)
- National Institutes of Health (K01 HL135455)
- American Heart Association (13SDG17340025)
- American Heart Association (19CDA34760019)
This publication has 64 references indexed in Scilit:
- Familial dilated cardiomyopathy: Current challenges and future directionsGlobal Cardiology Science & Practice, 2012
- Lamins at a glanceJournal of Cell Science, 2012
- Patient-Specific Induced Pluripotent Stem Cells as a Model for Familial Dilated CardiomyopathyScience Translational Medicine, 2012
- Vascular endothelial dysfunction in Duchenne muscular dystrophy is restored by bradykinin through upregulation of eNOS and nNOSBasic Research in Cardiology, 2011
- Gene expression, chromosome position and lamin A/C mutationsNucleus, 2011
- Cardiovascular Pathology in Hutchinson-Gilford Progeria: Correlation With the Vascular Pathology of AgingArteriosclerosis, Thrombosis, and Vascular Biology, 2010
- Clinical and genetic issues in dilated cardiomyopathy: A review for genetics professionalsGenetics in Medicine, 2010
- Assessing Endothelial Vasodilator Function with the Endo-PAT 2000Journal of Visualized Experiments, 2010
- A novel mutation in LAMIN A/C is associated with isolated early-onset atrial fibrillation and progressive atrioventricular block followed by cardiomyopathy and sudden cardiac deathHeart Rhythm, 2009
- Lamin A/C haploinsufficiency causes dilated cardiomyopathy and apoptosis-triggered cardiac conduction system diseaseJournal of Molecular and Cellular Cardiology, 2008