Reduced cardiac antioxidant defenses mediate increased susceptibility to workload-induced myocardial injury in males with genetic cardiomyopathy.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1051165 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Ongoing cardiomyocyte injury is a major mechanism in the progression of heart failure, particularly in dystrophic hearts. Due to the poor regenerative capacity of the adult heart, cardiomyocyte death results in the permanent loss of functional myocardium. Understanding the factors contributing to myocyte injury is essential for the development of effective heart failure therapies. As a model of persistent cardiac injury, we examined mice lacking β-sarcoglycan (β-SG), a key component of the dystrophin glycoprotein complex (DGC). The loss of the sarcoglycan complex markedly compromises sarcolemmal integrity in this β-SG-/- model. Our studies aim to characterize the mechanisms underlying dramatic sex differences in susceptibility to cardiac injury in β-SG-/- mice. Male β-SG-/- hearts display significantly greater myocardial injury and death following isoproterenol-induced cardiac stress than female β-SG-/- hearts. This protection of females was independent of ovarian hormones. Male β-SG-/- hearts displayed increased susceptibility to exogenous oxidative stress and were significantly protected by angiotensin II type 1 receptor (AT1R) antagonism. Increasing general antioxidative defenses or increasing the levels of S-nitrosylation both provided protection to the hearts of β-SG-/- male mice. Here we demonstrate that increased susceptibility to oxidative damage leads to an AT1R-mediated amplification of workload-induced myocardial injury in male β-SG-/- mice. Improving oxidative defenses, specifically by increasing S-nitrosylation, provided protection to the male β-SG-/- heart from workload-induced injury. These studies describe a unique susceptibility of the male heart to injury and may contribute to the sex differences in other forms of cardiac injury.
2024-03-15 | GSE249946 | GEO
Project description:CPT1A Over-expression Increases Reactive Oxygen Species in the Mitochondria and Promotes Antioxidant Defenses in Prostate Cancer
| PRJNA676030 | ENA
Project description:We hope to determine the importance of different genes (including B receptors) in anthracycline-induced cardiomyopathy. This has important benefits to patients exposed to anthracyclines, as this could help determine whether certain individuals have increased susceptibility to cardiac injury.
| 2090060 | ecrin-mdr-crc
Project description:Lipid (Plasmalogen) levels can be modulated via a dietary supplement called alkylglycerols (AG) which has demonstrated benefits in some disease settings. However, its therapeutic potential in cardiomyopathy remains unknown. This study explored an optimized AG supplement in restoring plasmalogen levels and attenuate cardiac dysfunction/pathology. Here, we placed a cardiac-specific transgenic cardiomyopathy mouse model, with cardiac function and molecular landscape assessed. AG supplementation increased total plasmalogens in DCM hearts and attenuated lung congestion of both sexes, but only prevented cardiac dysfunction in males. This was associated with cardiac and renal enlargement, a more favorable pro-cardiac gene expression profile, and a trend for lower cardiac fibrosis. By lipidomics, specific d18:1 ceramide species associated with cardiac pathology were lower in the DCM hearts from mice on the AG diet, and tetra-linoleoyl cardiolipin, a lipid crucial for mitochondria function was restored with AG supplementation. Proteomic analysis of hearts from male DCM mice receiving AG supplementation revealed enrichment in mitochondrial protein network, as well as upregulation of extracellular matrix binding proteins associated with cardiac regeneration. Here we highlight that AG supplementation restored plasmalogens in DCM hearts, but showed greater therapeutic potential in males than females
2024-08-08 | MSV000095560 | MassIVE
Project description:In this study, we have created a mouse model of methamphetamine cardiomyopathy that reproduces the chronic, progressive dosing commonly encountered in addicted subjects. We gradually increased the quantity of methamphetamine given to C57Bl/6 mice from 5 to 40 mg/kg over five months. At the fifth month, heart weight was increased, echocardiograms showed a dilated cardiomyopathy and survival was lower in males, with less effect in females. Interestingly, these findings correspond to previous observations in human patients, suggesting greater male susceptibility to the effects of methamphetamine on the heart.Transcriptional analysis showed changes in genes dysregulated in previous methamphetamine neurological studies as well as many that likely play a role in cardiac response to this toxic stress. We expect that a deeper understanding of the molecular biology of methamphetamine exposure in the heart will provide insights into the mechanism of cardiomyopathy in addicts and potential routes to more effective treatment.
2018-09-01 | GSE109790 | GEO
Project description:A catalytic antioxidant (AEOL 10150) attenuates expression of inflammatory genes in stroke. White and grey matter in the distribution on the middle cerebral artery 6 hours after administration of the saline/catalytic antioxidant AEOL 10150 and ischemia/reperfusion of the MCAO; pooled mRNA from 6 brains. Keywords = stroke, antioxidant Keywords: repeat sample
2002-06-26 | GSE63 | GEO
Project description:gene expression profiles of lymphoblastoid cells from control males without autism Keywords: control males
2007-06-01 | GSE7317 | GEO
Project description:Men are at an increased risk of dying from heart failure caused by inflammatory heart diseases such as atherosclerosis, myocarditis and dilated cardiomyopathy (DCM). We previously showed that immune responses in the heart are phenotypically distinct in male compared to female mice 10 days after infection resulting in severe DCM in males. Groups consisted of Infected Males, Infected Females, Uninfected Males and Uninfected females. There are 3 mice per group. A total of 12 samples were analyzed in this experiment (12 for 10 dpi and 12 for 90 dpi).
2012-01-19 | E-GEOD-35182 | biostudies-arrayexpress
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