ScRNA-seq shows cardiac fibrosis and immune microenvironment activation in HCM mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE299323 | GEO | 2026/04/30
REPOSITORIES: GEO
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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:ScRNA-seq shows cardiac fibrosis and immune microenvironment activation in HCM mice
| PRJNA1273908 | ENA
Project description:Background Hypertrophic cardiomyopathy (HCM) is defined clinically by pathological left ventricular hypertrophy (LVH). We have previously developed a plasma proteomics biomarker panel that correlates with clinical markers of disease severity and sudden cardiac death (SCD) risk in adult patients with HCM. The aim of this study was to validate the adult biomarkers and perform new discovery proteomics in childhood-onset HCM. Methods Fifty-nine protein biomarkers were identified from an exploratory plasma proteomics screen in children with HCM and augmented into our existing multiplexed targeted liquid chromatography-tandem/mass spectrometry-based assay. The association of these biomarkers with clinical phenotypes and outcomes was prospectively tested in plasma collected from 148 children with HCM and 50 healthy controls. Machine learning techniques were used to develop novel paediatric plasma proteomic biomarker panels.Results Four previously validated adult HCM markers (Aldolase Fructose-Bisphosphate A, Complement C3a, Talin-1 and Thrombospondin 1) and three new markers (Glycogen Phosphorylase B, Lipoprotein A and Profilin 1) were elevated in paediatric HCM. Using supervised machine learning applied to training (n=137) and validation cohorts (n=61), this 7-biomarker panel differentiated HCM from healthy controls with an area under the curve of 1.0 in the training dataset (sensitivity 100% [95% confidence interval: 95–100]; specificity 100% [96–100]) and 0.82 in the validation dataset (sensitivity 75% [59–86]; specificity 88% [75–94]). Reduced circulating levels of 4 other peptides (Apolipoprotein L1-, Complement 5b-, Immunoglobulin Heavy Constant Epsilon- and Serum Amyloid A4-peptide) found in children with high SCD risk provided complete separation from the low and intermediate risk groups, and predicted mortality and adverse cardiovascular outcomes (hazard ratio 1.53 [1.2 –2.0], p = 0.001). ConclusionIn children, a 7-biomarker proteomics panel can distinguish HCM from controls with high sensitivity and specificity, and a second 4-biomarker panel identifies those at high risk of adverse outcomes, including sudden cardiac death.
2024-07-03 | PXD045304 | Pride
Project description:Dominant pathogenic variants encoding amino acid substitutions in cardiac myosin heavy chain cause hypertrophic cardiomyopathy (HCM), a currently incurable disorder that increases risk for stroke, heart failure, and sudden cardiac death. We assessed the efficacy of two different genetic therapies, an adenine base editor (ABE8e) and a potent Cas9 nuclease delivered by AAV9, to prevent disease in mice carrying the heterozygous HCM pathogenic variant myosin R403Q. One dose of dual AAV9 vectors, each carrying one half of RNA-guided ABE8e, corrected the pathogenic variant in ≥70% of ventricular cardiomyocytes and maintained durable, normal cardiac structure and function. An additional dose provided more global editing especially in the atria but also increased bystander editing. AAV9 delivery of RNA-guided Cas9 nuclease effectively inactivated the pathogenic allele, albeit with dose-dependent toxicities, necessitating a narrow therapeutic window to maintain health. These preclinical studies demonstrate considerable potential for single-dose genetic therapies to correct or silence pathogenic variants and prevent the development of HCM.
2022-12-13 | GSE220808 | GEO
Project description:Dominant pathogenic variants encoding amino acid substitutions in cardiac myosin heavy chain cause hypertrophic cardiomyopathy (HCM), a currently incurable disorder that increases risk for stroke, heart failure, and sudden cardiac death. We assessed the efficacy of two different genetic therapies, an adenine base editor (ABE8e) and a potent Cas9 nuclease delivered by AAV9, to prevent disease in mice carrying the heterozygous HCM pathogenic variant myosin R403Q. One dose of dual AAV9 vectors, each carrying one half of RNA-guided ABE8e, corrected the pathogenic variant in ≥70% of ventricular cardiomyocytes and maintained durable, normal cardiac structure and function. An additional dose provided more global editing especially in the atria but also increased bystander editing. AAV9 delivery of RNA-guided Cas9 nuclease effectively inactivated the pathogenic allele, albeit with dose-dependent toxicities, necessitating a narrow therapeutic window to maintain health. These preclinical studies demonstrate considerable potential for single-dose genetic therapies to correct or silence pathogenic variants and prevent the development of HCM.
2022-12-13 | GSE220811 | GEO
Project description:Dominant pathogenic variants encoding amino acid substitutions in cardiac myosin heavy chain cause hypertrophic cardiomyopathy (HCM), a currently incurable disorder that increases risk for stroke, heart failure, and sudden cardiac death. We assessed the efficacy of two different genetic therapies, an adenine base editor (ABE8e) and a potent Cas9 nuclease delivered by AAV9, to prevent disease in mice carrying the heterozygous HCM pathogenic variant myosin R403Q. One dose of dual AAV9 vectors, each carrying one half of RNA-guided ABE8e, corrected the pathogenic variant in ≥70% of ventricular cardiomyocytes and maintained durable, normal cardiac structure and function. An additional dose provided more global editing especially in the atria but also increased bystander editing. AAV9 delivery of RNA-guided Cas9 nuclease effectively inactivated the pathogenic allele, albeit with dose-dependent toxicities, necessitating a narrow therapeutic window to maintain health. These preclinical studies demonstrate considerable potential for single-dose genetic therapies to correct or silence pathogenic variants and prevent the development of HCM.
2022-12-13 | GSE220517 | GEO
Project description:The most common form of genetic heart disease is hypertrophic cardiomyopathy (HCM), which is caused by mutations in cardiac sarcomeric genes and leads to abnormal heart muscle thickening. Complications of HCM include heart failure, arrhythmia, and sudden cardiac death. The dominant-negative c.1208 G>A (p.R403Q) mutation in b-myosin (MYH7) is a common and well-studied mutation that leads to increased cardiac contractility and HCM onset. Here we identify an adenine base editor (ABE) and single-guide RNA system that can efficiently correct this human pathogenic mutation with minimal off-target and bystander editing. We show that delivery of base editing components rescues pathological manifestations of HCM in iPSC-cardiomyocytes derived from HCM patients and in a humanized mouse model of HCM. Our findings demonstrate the use of base editing to treat inherited cardiac diseases and prompt the further development of ABE-based therapies to correct a variety of monogenic mutations causing cardiac disease.
2022-10-25 | GSE201755 | GEO
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), a genetic heart disease defined by unexplained cardiac wall thickening, is a leading cause of sudden death worldwide. However, the three-dimensional organization of cardiac tissue underlying left ventricular hypertrophy remains poorly understood. We developed CaMVIA-3D, a deep-learning volumetric imaging and analysis pipeline to characterize cardiac microarchitecture. Analysis of tissues from HCM hearts revealed genotype-specific differences in cardiomyocyte volume, morphology, and extracellular volume, with pathogenic variants exhibiting greater concentric cellular hypertrophy and disarray, and variant-negative cases showing predominant fibrosis. Longitudinal profiling of a pig HCM model revealed early-onset fibrosis preceding cardiomyocyte hypertrophy. Integrating transcriptomic and morphologic changes, we identified genes associated with cellular and extracellular remodeling. These findings define genotype-specific microstructural differences in HCM, offering insights to improve diagnostics and targeted therapies.
2026-03-18 | GSE308244 | GEO
Project description:A soy diet worsens the progression of an inherited form of hypertrophic cardiomyopathy (HCM) in male mice when compared to casein-fed mice. Females are largely resistant to this diet effect and better preserve cardiac function. We hypothesized that the abundant phytoestrogens found in soy are mainly responsible for this diet-dependent phenotype. Indeed, feeding male mice a phytoestrogen-supplemented casein-based diet can recapitulate the negative outcome seen when male mice are fed a standard soy-based diet. To gain mechanistic insights into disease pathogenesis, we used Affymetrix microarrays to profile gene expression in left ventricular tissue from 2 month old HCM male and female mice as well as wild-type littermate controls. These mice were fed a phytoestrogen (genistein + daidzein)-supplemented casein-based diet. We identified a number of molecular pathways that could explain both the male and female phenotypes. Hearts from male and female wild-type or HCM C57BL/6 mice fed a phytoestrogen-supplemented (genistein and daidzein mix) casein-based diet were excised at 2 months of age. Total RNA was extracted from left ventricles. Biotin-labeled amplified RNA was hybridized to Affymetrix Mouse Genome 430 2.0 microarrays.
2011-06-02 | E-GEOD-29648 | biostudies-arrayexpress