Comparative analysis of mouse cardiac gene expression: diet, sex, and disease
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE25700 | GEO | 2010/12/01
SECONDARY ACCESSION(S): PRJNA134111
REPOSITORIES: GEO
Similar Datasets
Project description:The perception that soy food products and dietary supplements will have beneficial effects on heart health has led to a massive consumer market. However, we have previously noted that diet has a profound effect on disease progression in a genetic model of hypertrophic cardiomyopathy (HCM). In this model, a soy-based diet negatively impacts cardiac function in male mice. Given the frequent correlation between functional changes and transcriptional changes, we investigated the effect of diet (soy- vs. milk-based) on cardiac gene expression and how it relates to the additional factors of sex and disease. We found that gene expression in the heart is altered more by diet than by sex or an inherited disease. We also found that the healthy male heart may be sensitized to dietary perturbations of gene expression in that it displays a gene expression profile more similar to diseased hearts than to healthy female hearts. These observations may in part account for divergence in HCM phenotypes between males and females and between diets. Hearts from male and female wild-type or HCM C57BL/6 mice fed either a soy or casein-based diet were excised at 2 months of age. Total RNA was extracted from left ventricles. Biotin-labeled amplified RNA was hybridized to MG_U74Av2 Affymetrix microarrays.
2010-12-01 | E-GEOD-25700 | biostudies-arrayexpress
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
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.
2011-06-02 | GSE29648 | 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: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:Heart disease remains the number one killer of women in the US. Nonetheless, studies in women and female animal models continue to be underrepresented in cardiac research. Hypertrophic cardiomyopathy (HCM), the most commonly inherited cardiac disorder, has been tied to sarcomeric protein variants. Among the susceptible genes, TNNC1—encoding cardiac troponin C (cTnC)—has contributed to a substantial HCM phenotype in mice. In this study we sought to characterize the sexual dimorphism observed within cardiac physiology and transcriptomics of adult male and female mice bearing the HCM-associated cTnC-A8V point mutation. The HCM mice showed a significant decrease in stroke volume, left ventricular diameter, volume, and relative wall thickness. Importantly, isovolumetric contraction time was significantly higher for female HCM mice. RNA sequencing revealed several altered canonical pathways within the HCM mice vs WT groups including an increase in EIF2 signaling, ILK signaling, actin nucleation by ARP-WASP complex, regulation of actin-based motility by Rho, VDR/RXR activation, and glutathione redox reactions pathways. In contrast, Valine Degradation, TCA Cycle II, Methionine Degradation, and Inositol Phosphate Compound pathways were notably down regulated in HCM mice. HCM male vs. female mice followed similar trends of the canonical pathways altered between the HCM and WT. Interestingly, seven of the genes that were differentially expressed in both the WT and HCM male vs female comparisons changed directions in fold change between the sexes. These data suggest a sexually-dimorphic HCM phenotype and identify several key pathways and genes that could be critical to sex differences seen in disease manifestation.
2020-01-23 | GSE144098 | 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:Hypertrophic cardiomyopathy (HCM) is a complex disease partly explained by the effects of individual gene variants on sarcomeric protein biomechanics. At the cellular level, HCM mutations most commonly enhance force production, leading to higher energy demands. Despite significant advances in elucidating sarcomeric structure-function relationships, there is still much to be learned about the mechanisms that link altered cardiac energetics to HCM phenotypes. In this work, we test the hypothesis that changes in cardiac energetics represent a common pathophysiologic pathway in HCM. We performed a comprehensive multi-omics profile of the molecular (transcripts, metabolites, and complex lipids), ultrastructural, and functional components of HCM energetics using myocardial samples from 27 HCM patients and 13 normal controls (donor hearts). Integrated omics analysis revealed alterations in a wide array of biochemical pathways with major dysregulation in fatty acid metabolism, reduction of acylcarnitines, and accumulation of free fatty acids. HCM hearts showed evidence of global energetic decompensation manifested by a decrease in high energy phosphate metabolites (ATP, ADP, and phosphocreatine) and a reduction in mitochondrial genes involved in the creatine kinase and ATP synthesis. Accompanying these metabolic derangements, quantitative electron microscopy showed an increased fraction of severely damaged mitochondria with reduced cristae density, coinciding with reduced citrate synthase (CS) activity and mitochondrial oxidative respiration. These mitochondrial abnormalities were associated with elevated reactive oxygen species (ROS) and reduced antioxidant defenses. However, despite significant mitochondrial injury, HCM hearts failed to upregulate mitophagic clearance. Overall, our findings suggest that perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in patients with HCM. These results highlight potential new drug targets for attenuation of the clinical disease through improving metabolic function and reducing mitochondrial injury.
2022-07-17 | GSE180313 | GEO
Project description:Male and female disease states differ in their prevalence, treatment responses, and survival rates. In cardiac disease, women almost uniformly fare far worse than men1-3. Though sex plays a critical role in cardiac disease, the mechanisms underlying sex differences in cardiac homeostasis and disease remain unexplained. Here, we reveal sex-specific cardiac transcriptomes and proteomes and show that cardiac sex differences are predominately controlled via post-transcriptional mechanisms. Using a quantitative proteomics-based approach, we characterize differential sex-specific enriched cardiac proteins, protein complexes, and biological sex processes in the context of global genetic diversity of the Collaborative Cross. We show that differences in cardiac protein expression are established by both hormonal and genetic mechanisms and define two additional pathways, one that is SRY dependent and one that is SRY-independent. We also determined the onset of sex-biased protein expression and discovered that sex disparities in heart tissue occur at the earliest stages of heart development, during the period preceding primary mammalian sex determination. This may explain why congenital heart disease, a leading cause of death whose origin is often developmental, is sex biased. Our results reveal the molecular foundations for the differences in cardiac tissue that underlie sex disparities in health, disease, and treatment outcomes.
2022-08-11 | PXD020139 | Pride
Project description:Cardiac function of mice fed with a 60%fat diet (high fat diet, HFD) for 16 weeks was analyzed. Hearts showed an alteration in ejection fraction and an increase in left ventricular en systolic diameter. However mice injected with an AAV overexpressing microRNA-322 (miR-322) were protected: ejection fraction was less decreased and LVESD less increased than in animals treated with an AAV control or an AAVsponge anti miR-322 (which decrease miR-322 availability and action in the heart). To better understand globla changes induced by miR-322 modulation in the heart, a transcriptomic analysis was performed to compare gene expression in three hearts from HFD+AAVmiR-322 mice (showing cardiac protection) and gene expression in three hearts from HFD+AAvsponge (were miR-322 action is decreased and showing the most altered cardiac function).
2014-10-02 | E-MTAB-2966 | biostudies-arrayexpress