Key result
Molecular profiling revealed distinct allele-specific gene expression in two mouse models of hypertrophic cardiomyopathy, with marked differences compared to human myectomy tissue where only two genes were similarly dysregulated.
Why the study?
Hypertrophic cardiomyopathy is characterized by phenotypic heterogeneity, prompting investigation into the molecular basis of the cardiac phenotype in mouse models and human myectomy tissue.
Observational (n=146)
Answers are grounded in this paper and cite their sources.
Caution against extrapolating mouse HCM models to humans; leaves open species-specific pathway validation.
Hypertrophic cardiomyopathy (HCM) is characterized by phenotypic heterogeneity. We investigated the molecular basis of the cardiac phenotype in two mouse models at established disease stage (mouse-HCM), and human myectomy tissue (human-HCM). We analyzed the transcriptome in 2 mouse models with non-obstructive HCM (R403Q-MyHC, R92W-TnT)/littermate-control hearts at 24 weeks of age, and in myectomy tissue of patients with obstructive HCM/control hearts (GSE36961, GSE36946). Additionally, we examined myocyte redox, cardiac mitochondrial DNA copy number (mtDNA-CN), mt-respiration, mt-ROS generation/scavenging and mt-Ca 2+ handling in mice. We identified distinct allele-specific gene expression in mouse-HCM, and marked differences between mouse-HCM and human-HCM. Only two genes ( CASQ1, GPT1) were similarly dysregulated in both mutant mice and human-HCM. No signaling pathway or transcription factor was predicted to be similarly dysregulated (by Ingenuity Pathway Analysis) in both mutant mice and human-HCM. Losartan was a predicted therapy only in TnT-mutant mice. KEGG pathway analysis revealed enrichment for several metabolic pathways, but only pyruvate metabolism was enriched in both mutant mice and human-HCM. Both mutant mouse myocytes demonstrated evidence of an oxidized redox environment. Mitochondrial complex I RCR was lower in both mutant mice compared to controls. MyHC-mutant mice had similar mtDNA-CN and mt-Ca 2+ handling, but TnT-mutant mice exhibited lower mtDNA-CN and impaired mt-Ca 2+ handling, compared to littermate-controls. Molecular profiling reveals differences in gene expression, transcriptional regulation, intracellular signaling and mt-number/function in 2 mouse models at established disease stage. Further studies are needed to confirm differences in gene expression between mouse and human-HCM, and to examine whether cardiac phenotype, genotype and/or species differences underlie the divergence in molecular profiles.
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Vakrou et al. (2021) conducted an observational in Hypertrophic cardiomyopathy (n=146). Hypertrophic cardiomyopathy (HCM) mutations vs. Healthy controls / littermate controls was evaluated on Differential gene expression (transcriptome). Molecular profiling revealed distinct allele-specific gene expression in two mouse models of hypertrophic cardiomyopathy, with marked differences compared to human myectomy tissue where only two genes were similarly dysregulated.
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