Deep-learning Analysis of 3D Microarchitectural Remodeling in Hypertrophic Cardiomyopathy
Ontology highlight
ABSTRACT:
ORGANISM(S): Sus scrofa
PROVIDER: GSE308244 | GEO | 2026/03/18
REPOSITORIES: GEO
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| GSE308244_RAW.tar | Raw | |||
| filelist.txt | Txt |
Items per page: 5 1 - 3 of 3 |
Similar Datasets
Project description:Background: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disorder, characterized by cardiomyocyte hypertrophy, cardiomyocyte disarray and fibrosis, which has a prevalence of ~1:200-500 and predisposes individuals to sudden death and heart failure. The mechanisms through which diverse HCM-causing mutations cause cardiac dysfunction remain mostly unknown and their identification may reveal new therapeutic avenues. MicroRNAs have emerged as critical regulators of gene expression and disease phenotype in various pathologies. We explored whether miRNAs could play a role in HCM pathogenesis and offer potential therapeutic targets. Methods and Results: Using high-throughput miRNA expression profiling and qPCR analysis in two distinct mouse models of HCM, we found that miR-199a-3p expression levels are upregulated in mutant mice compared to age- and treatment-matched wild-type mice. We also found that miR-199a-3p expression is enriched in cardiac non-myocytes compared to cardiomyocytes. When we expressed miR-199a-3p mimic in cultured primary cardiac non-myocytes and analyzed the conditioned media by proteomics, we found that several ECM proteins (e.g., TSP2, FBLN3, COL11A1, LYOX) were differentially expressed. We confirmed our proteomics findings by qPCR analysis of selected mRNAs and demonstrated that miR-199a-3p mimic expression in cardiac non-myocytes drives upregulation of ECM genes including Tsp2, Fbln3, Pcoc1, Col1a1 and Col3a1. To examine the role of miR-199a-3p in vivo, we inhibited its function using lock-nucleic acid (LNA)-based inhibitors (antimiR-199a-3p) in an HCM mouse model. Our results revealed that progression of cardiac fibrosis is attenuated when miR-199a-3p function is inhibited in mild-to-moderate HCM. Finally, guided by computational target prediction algorithms, we identified mRNAs Cd151 and Itga3 as direct targets of miR-199a-3p and have shown that miR-199a-3p mimic expression negatively regulates AKT activation in cardiac non-myocytes. Conclusions: Altogether, our results suggest that miR-199a-3p may contribute to cardiac fibrosis in HCM through its actions in cardiac non-myocytes. Thus, inhibition of miR-199a-3p in mild-to-moderate HCM may offer therapeutic benefit in combination with complementary approaches that target the primary defect in cardiac myocytes.
2024-01-26 | PXD042904 | Pride
Project description:Background – Hypertrophic cardiomyopathy (HCM) is a common genetic cardiac disorder that is characterized by the presence of left ventricular hypertrophy with histological evidence of myocyte disarray and fibrosis. Pathologic DNA variants in sarcomeric genes are seen in 50–60% of families, but the mechanistic origins of hypertrophy and disarray remain poorly understood. More molecular insights could contribute to a better understanding of these origins and improve therapeutic strategies for HCM. Methods – To identify gene expression patterns relevant to HCM pathology, we quantified intercellular heterogeneity in cardiomyocyte gene expression by performing single-cell RNA sequencing (scRNA-seq) on myectomy tissue from HCM patients. Results – Septal myectomy samples provide a unique opportunity to access diseased human heart tissue for scRNA-seq. We analysed gene expression of individual cardiomyocytes for three HCM patients, who each showed a similar presence of cardiomyocyte subpopulations. This similarity indicated these subpopulations emerge from biological processes, and not from experimental variability. Moreover, our data revealed functional links between genes important to HCM. A subpopulation characterized by elevated titin (TTN) expression showed increased expression of genes involved in muscle contraction and development. A subpopulation of Natriuretic Peptide A (NPPA)-enriched cells showed elevated expression of Natriuretic Peptide B (NPPB). Further analysis of gene co-expression revealed five groups of genes with tightly correlated expression (regulons), one consisting of mostly sarcomeric genes and another containing some well-known stress markers. These correlations were confirmed in 97 additional HCM myectomy samples and allowed us to de novo identify transcription factors related to sarcomeric gene expression and stress. Finally, using forward scatter, we charted functional implications of regulon expression and showed a link between the stress-marker regulon and cell size. Histology samples independently confirmed that regulon member skeletal alpha actin (ACTA1) correlates with cell size. Conclusion – We have shown that single-cell sequencing on myectomy samples from HCM patients identified new functional links between genes, transcription factors, and a functional link between genes and cell size. This highlights the relevance of cardiomyocyte heterogeneity, and additionally provides a wealth of novel insights into molecular events at the base of HCM, which potentially contribute to understanding disease progression.
2022-04-21 | GSE138262 | GEO
Project description:Left ventricular hypertrophy, myocardial disarray and interstitital fibrosis are the hallmarks of hypertrophic cardiomyopathy (HCM). Access to the myocardium for diagnostic purposes is limited. Circulating biomolecules reflecting the myocardial disease processes could improve early detection of HCM. Circulating miRNAs have been found to reflect disease processes in several cardiovascular diseases. Circulating miR-1, miR-495-3p and miR-4454 levels are elevated in plasma of HCM patients. miR-4454 is suggested as a potential biomarker for fibrosis in these patients.
2021-11-20 | GSE188324 | GEO
Project description:Alterations of serine/threonine phosphorylation of the cardiac proteome are a hallmark of heart failure. However, the contribution of tyrosine phosphorylation (pTyr) to the pathogenesis of cardiac hypertrophy remains unclear. We use global mapping to discover and quantify site-specific pTyr in two cardiac hypertrophic mouse models, i.e., cardiac overexpression of ErbB2 (TgErbB2) and myosin heavy chain R403Q (R403Q-aMyHC Tg), compared to control hearts. From this, there are significant phosphoproteomic alterations in TgErbB2 mice in right ventricular cardiomyopathy, hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM) pathways. On the other hand, R403Q-aMyHC Tg mice indicated that the EGFR1 pathway is central for cardiac hypertrophy, along with angiopoietin, ErbB, growth hormone, and chemokine signaling pathways activation. Surprisingly, most myofilament proteins have downregulation of pTyr rather than upregulation. Kinase-substrate enrichment analysis (KSEA) shows a marked downregulation of MAPK pathway activity downstream of k-Ras in TgErbB2 mice and activation of EGFR, focal adhesion, PDGFR, and actin cytoskeleton pathways. In vivo ErbB2 inhibition by AG-825 decreases cardiomyocyte disarray. Serine/threonine and tyrosine phosphoproteome confirms the above-described pathways and the effectiveness of AG-825 treatment. Thus, altered pTyr may play a regulatory role in cardiac hypertrophic models.
2023-03-10 | PXD036506 | Pride
Project description:Hypertrophic cardiomyopathy (HCM) constitutes the most common genetic cardiac disorder. However, current pharmacotherapeutics are mainly symptomatic and only partially address underlying molecular mechanisms. Circular RNAs (circRNAs) are a recently discovered class of non-coding RNAs and emerged as specific and powerful regulators of cellular functions. By performing global circRNA-specific next generation sequencing in cardiac tissue of patients with hypertrophic cardiomyopathy compared to healthy donors, we identified circZFPM2 (hsa_circ_0003380. CircZFPM2, which derives from the ZFPM2 locus, is a highly conserved regulatory circRNA that is strongly induced in HCM tissue. In vitro loss-of-function experiments were performed in neonatal rat cardiomyocytes, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), and HCM-patient-derived hiPSC-CMs. A knockdown of circZFPM2 was found to induce cardiomyocyte hypertrophy and compromise mitochondrial respiration, leading to an increased production of reactive oxygen species and apoptosis. In contrast, delivery of recombinant circZFPM2, packaged in lipid-nanoparticles or using AAV-based overexpression, rescued cardiomyocyte hypertrophic gene expression and promoted cell survival. Additionally, HCM-derived cardiac organoids exhibited improved contractility upon CM-specific overexpression of circZFPM2. Multi-Omics analysis further promoted our hypothesis, showing beneficial effects of circZFPM2 on cardiac contractility and mitochondrial function. Collectively, our data highlight that circZFPM2 serves as a promising target for the treatment of cardiac hypertrophy including HCM.
2024-04-25 | GSE261129 | GEO
Project description:Aims: Hypertrophic cardiomyopathy (HCM) caused by autosomal-dominant mutations in genes coding for structural sarcomeric proteins, is the most common inherited heart disease. HCM is associated with progressive myocardial hypertrophy, fibrosis, ventricular dysfunction, and arrhythmias. Hypoxia together with hypoxia-inducible transcription factor-1a (HIF1A) is the central master regulators of cellular hypoxia response and associated with HCM. Yet their exact role remains to be elucidated. Therefore, the effect of a cardiomyocyte-specific Hif-1a knockout (cHif1aKO) was studied in an established α-MHC719/+ HCM mouse model that exhibits the classical features of human HCM. Results: HIF-1α protein and HIF downstream targets were upregulated in left ventricular tissue of α-MHC719/+ mice. Cardiomyocyte-specific abolishment of Hif-1a did not cause cardiac abnormalities in wild type (WT) mice and resulted in amelioration of disease phenotype in α-MHC719/+ mice, as evidenced by decreased left ventricular wall thickness, reduced myocardial fibrosis, reduced disordered SRX/DRX state and diminished ROS production. In addition, cHif1aKO induced normalization of pro-hypertrophic and pro-fibrotic left ventricular remodeling signaling evidenced on whole transcriptome and proteomics analysis in α-MHC719/+ mice. Proteomics of serum samples from patients with early onset HCM compared to age-and gender-matched healthy controls revealed significant upregulation of HIF targets IGF2, LTBP1, RECK and downregulation of WDR1. Innovation and Conclusion: Overall, these results demonstrate for the first time that HIF signaling is involved in mouse and human HCM pathogenesis. Cardiomyocyte-specific knockout of Hif-1a attenuates disease phenotype in the HCM α-MHC719/+ mouse model. Targeting HIF-1α might serve as a therapeutic option to mitigate HCM disease progression.
2025-01-22 | GSE266649 | GEO
Project description:An important event in the pathogenesis of heart failure is the development of pathological cardiac hypertrophy. In cultured cardiac cardiomyocytes, the transcription factor Gata4 is required for agonist-induced cardiomyocyte hypertrophy. We hypothesized that in the intact organism Gata4 is an important regulator of postnatal heart function and of the hypertrophic response of the heart to pathological stress. To test this hypothesis, we studied mice heterozygous for deletion of the second exon of Gata4 (G4D). At baseline, G4D mice had mild systolic and diastolic dysfunction associated with reduced heart weight and decreased cardiomyocyte number. After transverse aortic constriction (TAC), G4D mice developed overt heart failure and eccentric cardiac hypertrophy, associated with significantly increased fibrosis and cardiomyocyte apoptosis. Inhibition of apoptosis by overexpression of the insulin-like growth factor 1 receptor prevented TAC-induced heart failure in G4D mice. Unlike WT-TAC controls, G4D-TAC cardiomyocytes hypertrophied by increasing in length more than width. Gene expression profiling revealed upregulation of genes associated with apoptosis and fibrosis, including members of the TGF? pathway. Our data demonstrate that Gata4 is essential for cardiac function in the postnatal heart. After pressure overload, Gata4 regulates the pattern of cardiomyocyte hypertrophy and protects the heart from load-induced failure. Experiment Overall Design: We reasoned that if Gata4 was a crucial regulator of pathways necessary for cardiac hypertrophy, then modest reductions of Gata4 activity should result in an observable cardiac phenotype. To test this hypothesis, we used gene targeted mice that express reduced levels of Gata4. We characterized these mice at baseline and after pressure Experiment Overall Design: overload.
2007-11-13 | E-GEOD-5500 | biostudies-arrayexpress
Project description:Hypertrophic cardiomyopathy (HCM) caused by autosomal-dominant mutations in genes that code for the structural proteins of the sarcomere, is the most common inherited heart disease. HCM is associated with progressive myocardial hypertrophy and fibrosis, ventricular dysfunction, and arrhythmias. Disease onset during childhood and adolescence carries the risk of morbidity and sudden cardiac death. Hypoxia and the main regulator of the cellular hypoxic response hypoxia-inducible transcription factor-1a (HIF1A) have been associated with HCM, however their exact roles are not elucidated yet.
2025-01-20 | PXD038911 | Pride
Project description:Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular (LV) hypertrophy and diastolic dysfunction, which leads to LV outflow tract obstruction (LVOTO) in the majority of cases. Mutations in genes encoding sarcomeric proteins cause HCM and are identified in more than half of the patients (sarcomere-mutation positive, SMP). Currently, more than 1500 HCM-causing mutations are known. Approximately 80% of mutations are located in the MYH7 and MYBPC3 genes, encoding for the thick filament proteins β-myosin heavy chain (β-MHC) and cardiac myosin-binding protein C (cMyBP-C), respectively. Less frequent are mutations in the TNNT2 and TNNI3 genes, encoding for the thin filament proteins cardiac troponin T (cTnT) and I (cTnI). Here, we applied an unbiased proteomics approach in a large number of myectomy samples from a clinically well-characterized HCM patient group to define HCM-specific derailments as well as genotype-specific changes at protein level. Our study shows that the downregulation of metabolic pathways and the upregulation of extracellular matrix proteins are the most prominent HCM-specific disease characteristics that are present in all samples independent of their genotype.
2021-01-14 | PXD012467 | Pride
Project description:Hypertrophic cardiomyopathy (HCM) is one of the most frequent inherited heart condition and a well-established risk factor for cardiovascular mortality worldwide. Although hypertrophy is traditionally regarded as an adaptive response to increased workload caused by physiological or pathological stress, prolonged hypertrophy can lead to heart failure characterized by impaired systolic function, increased apoptosis, fibrosis, ventricular dilation, and impaired metabolic substrate flexibility. While the key regulators for cardiac hypertrophy are well studied, the role of Prdm16 in this process remains poorly understood. In the present study, we demonstrate that Prdm16 is dispensable for cardiac development. However, it is required in the adult heart to preserve mitochondrial function and inhibit hypertrophy with advanced age. Cardiac-specific deletion of Prdm16 results in cardiac hypertrophy, excessive ventricular fibrosis, mitochondrial dysfunction, and impaired metabolic flexibility, leading to heart failure. We demonstrate that Prdm16 and euchromatic histone-lysine N- methyltransferase factors (Ehmts) act together to reduce the expression of fetal genes reactivated in pathological hypertrophy by inhibiting the functions of pro- hypertrophic transcription factor Myc. Although young Prdm16 knockout mice show normal cardiac function, they are predisposed to develop heart failure in response to metabolic stress. Collectively, our results demonstrate that Prdm16 protects the heart against age-dependent cardiac hypertrophy, fibrosis, mitochondrial dysfunction, adverse metabolic remodeling, and heart failure.
2020-09-21 | GSE153988 | GEO