Impaired vitamin D signaling causes LMNA mutation-related cardiomyopathy
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ABSTRACT:
PROVIDER: PRJNA755320 | ENA |
REPOSITORIES: ENA
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Project description:Mutations of the lamin A/C gene (LMNA) cause a variety of diseases including dilated cardiomyopathy (DCM). LMNA-related DCM often leads to severe heart failure, but the underlying pathophysiology is unknown. Here we show that vitamin D receptor (VDR) signaling is critically involved in LMNA-related DCM. We established iPS cells from DCM patients with an LMNA mutation and found that the iPS cell-derived cardiomyocytes (iPSCMs) showed remarkable DNA damage and reduced contractility compared with the isogenic control. Screening of a chemical library revealed that vitamin D2 reduced DNA damage of the mutant iPSCMs. RNA sequencing analysis showed that expression levels of putative downstream genes of VDR including DNA repair factors were downregulated in the mutant iPSCMs, which were upregulated by vitamin D2. Protein-protein interaction screening revealed that the binding of VDR to mutant LMNA was more robust than to wild-type LMNA, resulting in attenuated VDR signaling in the mutant iPSCMs. Vitamin D2 administration reduced DNA damage and improved cardiac function in pressure overload-induced heart failure mice. These results indicate that impaired DNA repair caused by reduced transcriptional activity of VDR induces cardiac dysfunction of LMNA-related DCM and suggest that VDR signaling is a potential therapeutic target for patients with DCM and heart failure.
2025-03-01 | GSE182219 | GEO
Project description:Mutations in the LMNA gene encoding nuclear lamins A/C cause a diverse array of tissue-selective diseases, with the heart being the most commonly affected organ. Despite progress in understanding the molecular perturbations emanating from LMNA mutations, an integrative understanding of the pathogenesis leading to cardiac dysfunction remains elusive. Using a novel cell-type specific Lmna deletion mouse model capable of translatome profiling, we found that cardiomyocyte-specific Lmna deletion in adult mice led to rapid cardiomyopathy with pathological remodeling. Prior to the onset of cardiac dysfunction, lamin A/C-depleted cardiomyocytes displayed nuclear envelope deterioration, disruption of the ER-golgi interface, and ER stress. Translatome profiling identified upregulation of Med25, a transcriptional co-factor involved in unfolded protein responses. Culturing Lmna-deleted cardiomyocytes in stiff hydrogels recapitulated these pathological features, confirming that cardiomyocyte-extrinsic factors contribute to the pathogenesis. Pharmacological activation of autophagy or modulation of ER stress significantly improved the cardiac function. These studies support a unified hypothesis wherein cardiomyopathy develops from autophagic impairment that exacerbates ER stress emanating from nuclear envelope deterioration.
2022-10-11 | GSE185620 | GEO
Project description:Vitamin D/Vitamin D Receptor (VDR) Axis Regulates LMNA gene expression
| PRJNA308852 | ENA
Project description:Deletion of Lmna in PDGFRA+ cells cause dilated cardiomyoapthy.
2022-06-09 | GSE199078 | GEO
Project description:Deletion of the Lmna Gene in Fibroblasts Causes Senescence-Associated Dilated Cardiomyopathy
| PRJNA818297 | ENA
Project description:• Mutations in the LMNA gene encoding Lamin A and C (Lamin A/C), major components of the nuclear lamina, cause laminopathies including dilated cardiomyopathy (DCM), but the underlying molecular mechanisms have not been fully elucidated. Here, by leveraging single-cell RNA-seq, ATAC-seq, protein array, and electron microscopy analysis, we show that insufficient structural maturation of cardiomyocytes owing to trapping of transcription factor TEAD1 by mutant Lamin A/C at the nuclear membrane underlies the pathogenesis of Q353R- LMNA-related DCM. Inhibition of the Hippo pathway rescued the dysregulation of cardiac developmental genes by TEAD1 in LMNA-mutant cardiomyocytes. Single-cell RNA-seq of cardiac tissues from DCM patients with the LMNA mutation confirmed the dysregulated expression of TEAD1 target genes. Our results propose an intervention for transcriptional dysregulation as a potential treatment of LMNA-related DCM.
2023-03-06 | GSE190977 | GEO
Project description:Over 180 LMNA gene mutations have been identified in human diseases including cardiac and skeletal myopathies, lipodystrophies, and premature aging syndromes. Postulated mechanisms by which these mutations result in different phenotypes include perturbation of normal nuclear structure and chromosome organization, and gene activity. We investigated whether a cardiomyopathic LMNA mutation, E161K, displayed abnormal gene expression. We compared the gene expression profile in the E161K LMNA-mutant heart to that of an end stage LMNA-normal heart. We compared the gene expression levels between two end-stage cardiomyopathic hearts in order to detect the gene expression differences more likely to reflect the LMNA mutation state. A region of left ventricle tissue that was grossly less fibrotic and contained cardiomyocytes of the LMNA-mutant heart was selected for RNA isolation. A region of a male heart that was also end-stage dilated cardiomyopathy, but LMNA-normal and also devoid of obvious fibrosis was selected for RNA isolation. Two technical replicates were performed for each sample, and data were analyzed using two different normalization strategies (Mas5 and RMA).
2010-01-30 | E-GEOD-17476 | biostudies-arrayexpress
Project description:Interplay of stress responses underlying the development of LMNA cardiomyopathy
| PRJNA770090 | ENA
Project description:Dilated cardiomyopathy (DCM) is a severe, non-ischemic heart disease, which ultimately results in heart failure (HF). Pathological genetic variants in LMNA cause DCM, which currently lacks specific treatment. Perturbing candidates related to dysregulated pathways have shown to ameliorate LMNA DCM, but their long-term efficacy as potential therapeutic targets is unknown. Here, we evaluated 14 potential candidates including Lmna gene products, key signaling pathways, calcium handling, proliferation regulators and Lamin interacting proteins, in a cardiac-specific Lmna DCM model. The candidates with improved cardiac function were further assessed through survival analysis. After comparing cardiac function, marker gene expression, Tgfβ signaling pathway activation, fibrosis, inflammation, proliferation, and DNA damage, we uncovered that restored cardiac function significantly correlated with suppression of HF/fibrosis marker expression and cardiac fibrosis in Lmna DCM. Interestingly, Lamin C or Sun1 shRNA administration achieved consistent, prolonged survival which highly correlated with reduced heart inflammation and DNA damage. In addition to Sun1 shRNA, perturbing the interaction between the nucleoskeleton and cytoskeleton via the KASH domain of Nesprin1 also effectively suppressed Lmna DCM. In contrast, Lamin A supplementation did not rescue long term survival and may impart a detrimental cardiotoxicity risk. Furthermore, transcriptome profiling was used to compare the differences between Lamin A and Lamin C treatment. Mechanistically, we identified that this lapse was attributed to a dose-dependent toxicity of Lamin A, which was independent of its maturation. This study highlights the potential for advancing Lamin C and Sun1 as therapeutic targets for the treatment of LMNA DCM.
2024-08-11 | GSE240745 | GEO
Project description:Purpose: LMNA-DCM accounts for 5-10% of DCM cases and has an age-related penetrance whose onset typically appears between the ages of 30 and 40. However, the precise mechanisms linking the LMNA mutation to increased arrhythmogenicity are still unknown. Methods: We utilized human iPSC-CMs, hESC-CMs, and cardiac tissues with RNA-seq, ChIP-seq, and ATAC-seq technologies. Results: The electrophysiological studies of iPSC-CMs identify the LMNA mutation as a cause of increased arrhythmogenicity in mutant iPSC-CMs through abnormal calcium homeostasis. We find that the mutations in LMNA disrupt the global chromatin conformation, resulting in hyper-activation of the platelet-derived growth factor (PDGF) signaling pathway in LMNA-mutant iPSC-CMs. Inhibition of the PDGF signaling pathway can rescue the arrhythmic phenotype of mutant iPSC-CMs. Conclusions: These findings were corroborated in cardiac tissues from healthy and LMNA-DCM patients, thus confirming a novel mechanism of LMNA-DCM pathogenesis both in vitro and in vivo.
2020-07-17 | GSE101514 | GEO