{"doi":"10.1126/scitranslmed.aax9276","title":"Clinical trial in a dish using iPSCs shows lovastatin improves endothelial dysfunction and cellular cross-talk in LMNA cardiomyopathy","abstract":"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.","journal":"Science Translational Medicine","year":2020,"id":54344,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":105,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9529,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":278891,"name":"Chun Liu","orcid":"0000-0002-8242-3896","position":1,"is_corresponding":false},{"id":280251,"name":"Mohamed Ameen","orcid":null,"position":2,"is_corresponding":false},{"id":280252,"name":"Farhan Himmati","orcid":null,"position":3,"is_corresponding":false},{"id":278892,"name":"Joe Z. Zhang","orcid":"0000-0002-6615-290X","position":4,"is_corresponding":false},{"id":280253,"name":"Saereh Khanamiri","orcid":null,"position":5,"is_corresponding":false},{"id":253477,"name":"Jan-Renier Moonen","orcid":"0000-0002-0361-824X","position":6,"is_corresponding":false},{"id":278893,"name":"Alexa Wnorowski","orcid":"0000-0002-1652-4728","position":7,"is_corresponding":false},{"id":278894,"name":"Linling Cheng","orcid":"0000-0001-7585-1270","position":8,"is_corresponding":false},{"id":242372,"name":"June‐Wha Rhee","orcid":"0000-0002-7044-2985","position":9,"is_corresponding":false},{"id":278895,"name":"Sadhana Gaddam","orcid":"0000-0001-6477-0483","position":10,"is_corresponding":false},{"id":278896,"name":"Ke Wang","orcid":"0000-0002-5305-6791","position":11,"is_corresponding":false},{"id":278897,"name":"Karim Sallam","orcid":"0000-0003-3469-6571","position":12,"is_corresponding":false},{"id":278898,"name":"Jack Boyd","orcid":"0000-0002-3020-5280","position":13,"is_corresponding":false},{"id":271806,"name":"Y. Joseph Woo","orcid":"0000-0002-2506-492X","position":14,"is_corresponding":false},{"id":240970,"name":"Marlene Rabinovitch","orcid":"0000-0001-7886-7104","position":15,"is_corresponding":false},{"id":12998,"name":"Joseph C. Wu","orcid":"0000-0002-6068-8041","position":16,"is_corresponding":false},{"id":278890,"name":"Nazish Sayed","orcid":"0000-0002-8229-721X","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-18T21:03:43.037640Z","pmid":"32727917","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}