@article{bibcite_8486,
  author = {Nazish Sayed and Chun Liu and Mohamed Ameen and Farhan Himmati and Joe Z. Zhang and Saereh Khanamiri and Jan-Renier Moonen and Alexa Wnorowski and Linling Cheng and June-Wha Rhee and Sadhana Gaddam and Kevin C. Wang and Karim Sallam and Jack H. Boyd and Y. Joseph Woo and Marlene Rabinovitch and Joseph C. Wu},
  title = {Clinical trial in a dish using iPSCs shows lovastatin improves endothelial dysfunction and cellular cross-talk in LMNA cardiomyopathy},
  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){\textendash}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 Kr{\"u}ppel-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.},
  year = {2020},
  journal = {Science Translational Medicine},
  volume = {12},
  pages = {eaax9276},
  month = {2020-07-29},
  url = {https://www.science.org/doi/10.1126/scitranslmed.aax9276},
  doi = {10.1126/scitranslmed.aax9276},
}