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LAD-Ligation: A Murine Model of Myocardial Infarction
Published on: October 14, 2009
Clinical trial in a dish using iPSCs shows lovastatin improves endothelial dysfunction and cellular cross-talk in
Nazish Sayed1,2,3, Chun Liu4,2,3, Mohamed Ameen4,2
1Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. joewu@stanford.edu sayedns@stanford.edu.
Insights
Mutations in the LMNA gene cause cardiolaminopathy, leading to endothelial dysfunction. KLF2 agonists, like lovastatin, improved endothelial function and may treat this condition.
Area of Science:
- Cardiovascular Biology
- Stem Cell Biology
- Genetics
Background:
- LMNA gene mutations cause cardiolaminopathy, a condition affecting the heart.
- The role of LMNA in endothelial cells (ECs) and its contribution to disease are poorly understood.
- This study investigates the EC-specific phenotype in LMNA-related dilated cardiomyopathy (DCM).
Purpose of the Study:
- To characterize the endothelial cell (EC) phenotype in LMNA-related DCM.
- To identify molecular mechanisms underlying EC dysfunction in this condition.
- To explore potential therapeutic strategies targeting EC dysfunction.
Main Methods:
- Generated and characterized human induced pluripotent stem cell (iPSC)-derived ECs from patients with LMNA-related DCM.
- Utilized genome-edited isogenic iPSC lines to confirm disease causality.
- Employed ATAC-seq and RNA-seq to analyze gene expression and chromatin accessibility.
- Investigated the role of Krüppel-like factor 2 (KLF2) in EC dysfunction.
- Tested KLF2 agonists, including lovastatin, as a therapeutic intervention.
Main Results:
- Patients with LMNA-related DCM showed clinical endothelial dysfunction and impaired iPSC-EC function (angiogenesis, nitric oxide production).
- Genome editing confirmed LMNA's role in EC dysfunction; correction restored EC function.
- KLF2 was identified as a key transcription factor mediating EC dysfunction.
- Lovastatin treatment rescued EC dysfunction in vitro and improved endothelial function in patients.
- Co-culture of iPSC-ECs and iPSC-cardiomyocytes with lovastatin improved cardiomyocyte function.
Conclusions:
- Endothelial cell dysfunction and impaired EC-cardiomyocyte cross-talk contribute to LMNA-related DCM pathogenesis.
- Lovastatin demonstrates therapeutic potential for vascular dysfunction in cardiolaminopathy patients.
- Targeting endothelial dysfunction offers a novel therapeutic avenue for LMNA-related heart disease.
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.
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