02770nas a2200325   4500000000100000008004100001260001500042100001700057700001300074700001800087700001900105700001700124700002100141700002200162700002000184700001800204700001800222700001900240700001800259700001700277700001700294700001800311700002400329700001700353245013800370856006100508300001300569490000700582520185500589       2020                            d  c2020-07-291 aNazish Sayed1 aChun Liu1 aMohamed Ameen1 aFarhan Himmati1 aJoe Z. Zhang1 aSaereh Khanamiri1 aJan-Renier Moonen1 aAlexa Wnorowski1 aLinling Cheng1 aJune-Wha Rhee1 aSadhana Gaddam1 aKevin C. Wang1 aKarim Sallam1 aJack H. Boyd1 aY. Joseph Woo1 aMarlene Rabinovitch1 aJoseph C. Wu00aClinical trial in a dish using iPSCs shows lovastatin improves endothelial dysfunction and cellular cross-talk in LMNA cardiomyopathy  uhttps://www.science.org/doi/10.1126/scitranslmed.aax9276  aeaax92760 v123 aMutations 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.