Novel heart specific long non-coding RNAs contribute to pathogenesis of Arrhythmogenic Cardiomyopathy [ARVC patients' heart LV]
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PROVIDER: PRJNA419747 | ENA |
REPOSITORIES: ENA
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Project description:Arrhythmogenic cardiomyopathy (AC) is an inherited cardiomyopathy characterized by fibrofatty replacement predominantly involved in right ventricle and clinically by ventricular arrhythmias.In this study, we set out to characterize the cardiac novel long-noncoding RNAs using deep RNA sequencing data from human heart tissues. Particularly, we identified AC specific novel lncRNAs that contribute to AC pathophysiology by comparing the lncRNAs transcripts of nine AC explanted hearts (RV), five non-diseased donor hearts (RV), four non-AC failing hearts (dilated cardiomyopathy, RV). To dissect the roles of novel lncRNAs in ARVC from LV, we also include six non-diseased donor hearts (LV; GSE107125) and six ARVC explanted hearts (LV) in the analysis. In the identified novel AC lncRNAs, a large part of them are derived from enhancer regions and acting as cis- elements to potentially regulate lipogenesis or lipid metabolism related genes. Finally, we validated several of these AC specific novel lncRNAs and their potential targets in independent patient samples. Collectively, we identified high-confidence AC specific novel lncRNAs from human samples and suggest their potential roles as cis- elements in AC pathology. Further study of these novel AC lncRNAs could provide new opportunities for diagnosis and therapeutic intervention. Please note that the GSE107157 records represent the 'five non-diseased donor hearts (RV) and six non-diseased donor hearts (LV)' data.
2020-01-01 | GSE107311 | GEO
Project description:Arrhythmogenic cardiomyopathy (AC) is an inherited cardiomyopathy characterized by fibrofatty replacement predominantly involved in right ventricle and clinically by ventricular arrhythmias.In this study, we set out to characterize the cardiac novel long-noncoding RNAs using deep RNA sequencing data from human heart tissues. Particularly, we identified AC specific novel lncRNAs that contribute to AC pathophysiology by comparing the lncRNAs transcripts of nine AC explanted hearts (RV), five non-diseased donor hearts (RV), four non-AC failing hearts (dilated cardiomyopathy, RV). To dissect the roles of novel lncRNAs in ARVC from LV, we also include six non-diseased donor hearts (LV) and six ARVC explanted hearts (LV) in the analysis. In the identified novel AC lncRNAs, a large part of them are derived from enhancer regions and acting as cis- elements to potentially regulate lipogenesis or lipid metabolism related genes. Finally, we validated several of these AC specific novel lncRNAs and their potential targets in independent patient samples. Collectively, we identified high-confidence AC specific novel lncRNAs from human samples and suggest their potential roles as cis- elements in AC pathology. Further study of these novel AC lncRNAs could provide new opportunities for diagnosis and therapeutic intervention.
2020-01-01 | GSE107475 | GEO
Project description:Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy primarily of the right ventricle characterized through fibrofatty replacement of cardiomyocytes. The genetic etiology in ARVC patients is most commonly caused by dominant inheritance and high genetic heterogeneity. Though histological examinations of ARVC affected human myocardium reveals fibrolipomatous replacement, the molecular mechanisms leading to loss of cardiomyocytes are largely unknown. We therefore analyzed the transcriptomes of 6 ARVC specimen derived from heart transplantation candidates and compared our findings to 6 non-failing donor hearts (NF) which could not be transplanted for technical reasons. In addition, we compared our findings to 7 hearts from patients with idiopathic dilated cardiomyopathy. From each heart left (LV) and right ventricular (RV) myocardial samples were analyzed by Affymetrix HG-U133 Plus 2.0 arrays, adding up to six sample groups. Unsupervised cluster analyses of the six sample groups revealed a clear separation of NF and cardiomyopathy samples. However, in contrast to the other samples, unsupervised cluster analyses revealed no distinct expression pattern in LV and RV samples from ARVC-hearts. We further identified differentially expressed transcripts using t-tests and found transcripts separating diseased and NF ventricular myocardium. Of note, in failing myocardium only about 15-16% of the genes are commonly regulated compared to NF samples. In addition both cardiomyopathies are clearly distinct on the transcriptome level. Comparison of the expression patterns between the failing RV and LV using a paired t-test revealed a lack of major differences between LV and RV gene expression in ARVC hearts. Microarrays were used to elucidate the differences between non-failing control hearts and those, suffering from arrhythmogenic right ventricular cardiomyopathy (ARVC).
2011-11-30 | E-GEOD-29819 | biostudies-arrayexpress
Project description:Arrhythmogenic cardiomyopathy (AC) is an inherited cardiomyopathy characterized by fibrofatty replacement predominantly involved in right ventricle and clinically by ventricular arrhythmias.In this study, we set out to characterize the cardiac novel long-noncoding RNAs using deep RNA sequencing data from human heart tissues. Particularly, we identified AC specific novel lncRNAs that contribute to AC pathophysiology by comparing the lncRNAs transcripts of nine AC explanted hearts (RV), five non-diseased donor hearts (RV), four non-AC failing hearts (dilated cardiomyopathy, RV). To dissect the roles of novel lncRNAs in ARVC from LV, we also include six non-diseased donor hearts (LV) and six ARVC explanted hearts (LV) in the analysis. In the identified novel AC lncRNAs, a large part of them are derived from enhancer regions and acting as cis- elements to potentially regulate lipogenesis or lipid metabolism related genes. Finally, we validated several of these AC specific novel lncRNAs and their potential targets in independent patient samples. Collectively, we identified high-confidence AC specific novel lncRNAs from human samples and suggest their potential roles as cis- elements in AC pathology. Further study of these novel AC lncRNAs could provide new opportunities for diagnosis and therapeutic intervention.
2020-11-20 | GSE107125 | GEO
Project description:Novel heart specific long non-coding RNAs contribute to pathogenesis of Arrhythmogenic Cardiomyopathy
| PRJNA420232 | ENA
Project description:Novel heart specific long non-coding RNAs contribute to pathogenesis of Arrhythmogenic Cardiomyopathy [ARVC patients' heart RV]
| PRJNA420213 | ENA
Project description:Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy primarily of the right ventricle characterized through fibrofatty replacement of cardiomyocytes. The genetic etiology in ARVC patients is most commonly caused by dominant inheritance and high genetic heterogeneity. Though histological examinations of ARVC affected human myocardium reveals fibrolipomatous replacement, the molecular mechanisms leading to loss of cardiomyocytes are largely unknown. We therefore analyzed the transcriptomes of 6 ARVC specimen derived from heart transplantation candidates and compared our findings to 6 non-failing donor hearts (NF) which could not be transplanted for technical reasons. In addition, we compared our findings to 7 hearts from patients with idiopathic dilated cardiomyopathy. From each heart left (LV) and right ventricular (RV) myocardial samples were analyzed by Affymetrix HG-U133 Plus 2.0 arrays, adding up to six sample groups. Unsupervised cluster analyses of the six sample groups revealed a clear separation of NF and cardiomyopathy samples. However, in contrast to the other samples, unsupervised cluster analyses revealed no distinct expression pattern in LV and RV samples from ARVC-hearts. We further identified differentially expressed transcripts using t-tests and found transcripts separating diseased and NF ventricular myocardium. Of note, in failing myocardium only about 15-16% of the genes are commonly regulated compared to NF samples. In addition both cardiomyopathies are clearly distinct on the transcriptome level. Comparison of the expression patterns between the failing RV and LV using a paired t-test revealed a lack of major differences between LV and RV gene expression in ARVC hearts.
2011-11-30 | GSE29819 | GEO
Project description:Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited cardiac disease characterized by fibro-fatty replacement of the myocardium that causes heart failure and sudden cardiac death. The most aggressive subtype of ARVC is ARVC type 5 (ARVC5), caused by a p.S358L mutation in TMEM43. The function and localization of TMEM43 and the mechanism by which the p.S358L mutation causes the disease, are unknown.
2019-07-12 | GSE101301 | GEO
Project description:Pericardial fluid is enriched by biologically active molecules of cardiovascular origin including microRNAs. Investigation of the disease-specific extracellular microRNAs could shed light on the molecular processes underlying disease development. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease characterized by life-threatening arrhythmias and progressive heart failure development. The current data about the association between microRNAs and ARVC development are limited. We performed small RNA sequence analysis of microRNAs of pericardial fluid samples obtained during transcutaneous epicardial access for ventricular tachycardia (VT) ablation of six patients with definite ARVC and three post-infarction VT patients. Disease-associated microRNAs of pericardial fluid were identified. Enrichment analysis of differentially expressed microRNAs revealed their close linkage to cardiac diseases.
2021-03-09 | GSE164490 | GEO
Project description:Introduction: We have reported that iPSC-cardiac myocytes from patients with arrhythmogenic cardiomyopathy (ACM) mount an intense innate immune response under basal conditions in vitro. In addition, blocking innate immune signaling via NFκB prevents disease in a mouse model of ACM (Dsg2mut/mut mice). Here, we defined the relative pathogenic roles of immune signaling in cardiac myocytes vs. infiltrating inflammatory cells in Dsg2mut/mut mice. Methods: To define the role of immune signaling in cardiac myocytes, we bred Dsg2mut/mut mice with mice with cardiac myocyte-specific expression of a dominant-negative form of IκBα (DN-IκBα), which prevents nuclear translocation and, thereby, activation of NFκB signaling only in cardiac myocytes. To define the role of inflammatory cells in ACM, we focused on cells expressing C-C motif chemokine receptor-2 (CCR2+ cells), known to mediate adverse cardiac remodeling and fibrosis. We bred Dsg2mut/mut mice with germline deletion of Ccr2 mice (Ccr2-/- mice). We compared phenotypes in Dsg2mut/mut mice with double-mutant Dsg2mut/mut X DN-IκB and Dsg2mut/mut X Ccr2-/- lines. Results: Dsg2mut/mut mice develop marked myocardial fibrosis, reduced LV ejection fraction (EF) and many PVCs. These disease features were all normalized in Dsg2mut/mut X DN-IκB mice. Hearts of Dsg2mut/mut and Dsg2mut/mut X DN-IκB mice contained equal numbers of CD68+ macrophages, but Dsg2mut/mut hearts had many more CCR2+ cells. Cardiac myocyte expression of Tlr4 which activates NFκB, was increased in Dsg2mut/mut mice but not in Dsg2mut/mut X Ccr2-/- mice. Dsg2mut/mut X Ccr2-/- mice showed greatly reduced myocardial fibrosis and PVCs but LV EF was markedly depressed. This suggested that contractile dysfunction in ACM is due not only to loss of muscle but to immune signaling in viable cardiac myocytes as well. To test this hypothesis, we treated Dsg2mut/mut and Dsg2mut/mut X Ccr2-/- mice with the NFκB inhibitor Bay 11-7082. Before treatment, LV EFs were significantly reduced in both groups. Untreated Dsg2mut/mut mice had ongoing deterioration of LV function, whereas treated Dsg2mut/mut mice showed no further disease progression and actually had some improvement in contractile function. However, LV function in treated Dsg2mut/mut X Ccr2-/- mice was virtually normalized. Conclusions: NFκB signaling in cardiac myocytes drives myocardial injury, LV dysfunction and arrhythmias in Dsg2mut/mut mice. It also mobilizes CCR2+ cells to the heart, where they promote myocardial injury and arrhythmias. CCR2+ cells alter gene expression in cardiac myocytes. LV dysfunction in Dsg2mut/mut mice is caused not only by muscle loss but also by negative inotropic effects of inflammation mediated by NFκB in viable cardiac myocytes. These results have obvious implications for ACM patients and suggest that anti-inflammatory therapy may be beneficial even in patients with established disease.
2024-02-28 | GSE228048 | GEO