Clinical trial in a dish using iPSCs shows lovastatin improves endothelial dysfunction and cellular cross-talk in LMNA cardiomyopathy.
Clinical trial in a dish using iPSCs shows lovastatin improves endothelial dysfunction and cellular cross-talk in LMNA cardiomyopathy.
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DOI：
10.1126/scitranslmed.aax9276
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发表时间：
2020-07-29
影响因子：
17.1
通讯作者：
Wu JC
中科院分区：
文献类型：
--
作者：
Sayed N;Liu C;Ameen M;Himmati F;Zhang JZ;Khanamiri S;Moonen JR;Wnorowski A;Cheng L;Rhee JW;Gaddam S;Wang KC;Sallam K;Boyd JH;Woo YJ;Rabinovitch M;Wu JC
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-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 cardiomyocyte function when co-cultured with iPSC-ECs and lovastatin. These results suggest impaired crosstalk 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. Patient-specific iPSCs model endothelial dysfunction in lamin A and C-related dilated cardiomyopathy and identify lovastatin as a therapy.
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-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 cardiomyocyte function when co-cultured with iPSC-ECs and lovastatin. These results suggest impaired crosstalk 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. Patient-specific iPSCs model endothelial dysfunction in lamin A and C-related dilated cardiomyopathy and identify lovastatin as a therapy.
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影响因子：
7
作者：
Lund E;Oldenburg AR;Delbarre E;Freberg CT;Duband-Goulet I;Eskeland R;Buendia B;Collas P
通讯作者：
Collas P
DOI：
10.1007/978-1-62703-511-8_7
发表时间：
2013
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Churko JM;Burridge PW;Wu JC
通讯作者：
Wu JC
影响因子：
37.8
作者：
Kitani, Tomoya;Ong, Sang-Ging;Wu, Joseph C.
通讯作者：
Wu, Joseph C.
影响因子：
20.3
作者：
Dekker, RJ;van Soest, S;Horrevoets, AJG
通讯作者：
Horrevoets, AJG
DOI：
10.1161/atvbaha.113.301933
发表时间：
2013-09-01
影响因子：
8.7
作者：
Bidault, Guillaume;Garcia, Marie;Bereziat, Veronique
通讯作者：
Bereziat, Veronique