Mouse model for hypertrophic cardiomyopathy
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive HF-X
ORGANISM(S): Mus Musculus (mouse)
TISSUE(S): Heart
DISEASE(S): Hypertrophic Cardiomyopathy
SUBMITTER: 
Jan Bernd Stöckl
LAB HEAD: Thomas Fröhlich
PROVIDER: PXD038911 | Pride | 2025-01-20
REPOSITORIES: pride
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| HET_170.raw | Raw | |||
| HET_222.raw | Raw | |||
| HET_224.raw | Raw | |||
| HET_73.raw | Raw | |||
| HET_84.raw | Raw |
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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:Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease and a leading cause of sudden cardiac death in young adults. HCM has been linked to mutations in genes encoding sarcomeric proteins, but how different mutations can result in a similar clinical phenotype is unknown. Analysis of surgical heart tissue samples from HCM patients with severe outflow track obstruction using high-resolution mass spectrometry-based top-down proteomics revealed a common pattern of altered sarcomeric proteoforms across HCM tissues compared to non-failing donor heart tissues. Our data suggest that common pathways are associated with clinical phenotypes in patients diagnosed with obstructive HCM, opening the door for the development of interventions that target the HCM phenotype rather than the individual sarcomeric gene mutation.
2020-07-24 | MSV000085823 | MassIVE
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: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:The study investigates the effect of a heterozygous MYBPC3 mutation combined with Western diet feeding on protein expression in a HCM mouse model. Hypertrophic cardiomyopathy (HCM) is the most common inherited genetic heart disease, characterized by asymmetric left ventricular hypertrophy and diastolic dysfunction. It is generally accepted that HCM is caused by mutations in genes encoding sarcomere proteins (e.g. MYBPC3, MYH7). However, not all mutation carriers will develop HCM and, moreover, phenotypical variation in terms of clinical presentation is large. The phenotypical expression of HCM thus requires additional disease modifiers on top of a sarcomere gene mutation. Clinical reports identify obesity and related comorbidities (diabetes, hyperlipidemia, hypertension) as a major factor contributing to disease expression and severity. We aimed to mimic this situation in a HCM mouse model by feeding a Western diet (8 weeks) to mice carrying a heterozygous mutation in MYBPC3. These heterozygous mice are phenotype negative under normal conditions, but developed cardiac dysfunction and hypertrophy upon Western diet feeding. The main goal of this proteomic screening is to identify clusters of proteins and pathways that are down/upregulated specifically in the left ventricle of mice suffering from a mutation and Western diet feeding. Also, we are interested in protein expression differences caused solely by mutation or Western diet. Group 1 are Wild type mice that received normal chow; group 2 are heterozygous mice that received normal chow; group 3 are Wild type mice that received a Western diet; group 4 are heterozygous mice that received a Western diet.
2023-10-01 | PXD043345 | Pride
Project description:Rationale There is a need for new and better biomarkers for hypertrophic cardiomyopathy (HCM) which correlate more closely with disease progression as determined by clinical imaging and biohumoral information. We have used a combination of heart tissue and plasma proteomics to identify potential biomarkers for HCM and developed them into an exploratory targeted proteomic assay. Objective To identify informative staging biomarkers for HCM and develop them into a blood test. The test using 10 µl of plasma, was developed into a 10 min liquid chromatography-tandem/mass spectrometry (LC-MS/MS) assay to analyze multiple candidate biomarkers and evaluate their association with clinical phenotypes in patients with HCM. Methods and Results Myocardial tissue and plasma samples from patients with HCM and healthy volunteers (controls) were screened using a combined gel- and nano-LC quadrupole time of flight MS approach. Twenty-six potential biomarkers were identified from the proteomics screens and developed into a multiplexed targeted proteomic assay. Their association with clinical phenotypes was tested in plasma samples collected from 207 prospectively recruited participants: 110 patients with HCM (50.1 ± 15.0 years, 70% male; 48 [44%] with identified genetic mutations) and 97 controls (49.6 ± 13.4 years, 58% male), randomly split into training (80 HCM, 67 controls) and validation datasets (30 HCM, 30 controls). Six markers (Aldolase Fructose-Bisphosphate A, Complement C3, Glutathione S-Transferase Omega 1, Ras Suppressor Protein 1, Talin 1, and Thrombospondin 1) were significantly increased (P<0.006) in the plasma of HCM patients compared to controls in the training dataset. These markers correlated with left ventricular (LV) wall thickness, LV mass and % myocardial scar on cardiovascular magnetic resonance imaging. Using supervized machine learning (ML) this panel differentiated HCM from controls (area under the curve: 0.89 in the training dataset, sensitivity 96%, 95% confidence interval [CI] 77–93; specificity 87%, 95%CI 77–94; and 0.87 in the validation dataset, sensitivity 97%, 95%CI 83–100; specificity 77%, 95%CI 58–90). Four of the biomarkers as well as the composite ML score of the plasma proteome correlated with the presence of nonsustained ventricular tachycardia and the estimated 5-year risk of sudden cardiac death. Conclusion By developing a high-throughput, multiplex, and targeted proteomic plasma assay we identified 6 biomarkers that correlate with the presence of disease and with clinical risk score for sudden cardiac death.
2019-07-08 | PXD009859 | 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 | GSE220517 | GEO
Project description:BACKGROUND: MYBPC3 is one of the most mutated gene known to cause hypertrophic cardiomyopathy (HCM). However, the molecular mechanisms of how mutations in MYBPC3 lead to the onset and progression of HCM are poorly understood. Thus, advancing in-vitro studies to define these mechanisms of mutations leading to HCM are still warranted. Thus, the primary objective of this study was to investigate the molecular mechanisms underlying the pathogenesis of HCM associated with MYBPC3 mutation utilizing isogenic human-induced pluripotent stem cell (hiPSC)-derived cardiac organoids (hCOs).
2025-01-28 | GSE262876 | GEO
Project description:Cardiac biopsies were obtained from hypertrophic cardiomyopathy (HCM) patients and controls and subjected to mRNA profiling.
2024-11-12 | GSE249925 | GEO