Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA237182 | ENA |
REPOSITORIES: ENA
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Project description:In this study, we used a cardiac-specific, inducible expression system to activate YAP in adult mouse heart. Activation of YAP in adult heart promoted cardiomyocyte proliferation and did not deleteriously affect heart function. Furthermore, YAP activation after myocardial infarction (MI) preserved heart function and reduced infarct size. Using adeno-associated virus subtype 9 (AAV9) as a delivery vector, we expressed human YAP in the murine myocardium immediately after MI. We found that AAV9:hYAP significantly improved cardiac function and mouse survival. AAV9:hYAP did not exert its salutary effects by reducing cardiomyocyte apoptosis. Rather, we found that AAV9:hYAP stimulated adult cardiomyocyte proliferation. Gene expression profiling indicated that AAV9:hYAP stimulated cell cycle gene expression, enhanced TGFβ-signaling, and activated of components of the inflammatory response.Cardiac specific YAP activation after MI mitigated myocardial injury after MI, improved cardiac function and mouse survival. These findings suggest that therapeutic activation of hYAP or its downstream targets, potentially through AAV-mediated gene therapy, may be a strategy to improve outcome after MI. Three groups were involved in this study: sham group, AAV9:Luci+MI group and AAV9-YAP+MI group. Each group contained three biological replicates. The sham group had neither myocardial infarction nor AAV injection. The AAV9:Luci +MI(L for brief) group had myocardial infarction and injected with AAV9:Luic. The AAV9:hYAP+MI(YAP for brief) group had myocardial infarction and injected with AAV9:hYAP. 5 days after MI and AAV injection, the heart apexes were collected and the total RNA were isolated for microarray analysis.
2014-05-26 | E-GEOD-54612 | biostudies-arrayexpress
Project description:In this study, we used a cardiac-specific, inducible expression system to activate YAP in adult mouse heart. Activation of YAP in adult heart promoted cardiomyocyte proliferation and did not deleteriously affect heart function. Furthermore, YAP activation after myocardial infarction (MI) preserved heart function and reduced infarct size. Using adeno-associated virus subtype 9 (AAV9) as a delivery vector, we expressed human YAP in the murine myocardium immediately after MI. We found that AAV9:hYAP significantly improved cardiac function and mouse survival. AAV9:hYAP did not exert its salutary effects by reducing cardiomyocyte apoptosis. Rather, we found that AAV9:hYAP stimulated adult cardiomyocyte proliferation. Gene expression profiling indicated that AAV9:hYAP stimulated cell cycle gene expression, enhanced TGFβ-signaling, and activated of components of the inflammatory response.Cardiac specific YAP activation after MI mitigated myocardial injury after MI, improved cardiac function and mouse survival. These findings suggest that therapeutic activation of hYAP or its downstream targets, potentially through AAV-mediated gene therapy, may be a strategy to improve outcome after MI.
2014-05-26 | GSE54612 | GEO
Project description:Myocardial infarction (MI), which affects about 3 million people globally each year, permanently damages the heart and reduces cardiac function1. Recent studies have indicated that activating YAP in cardiomyocytes (CMs) promotes cardiac regeneration and mitigates pathological remodeling in mouse and pig MI models2,3. To precisely control YAP activity in vivo and encourage its clinical application, we developed an adeno-associated virus 9 (AAV9)-based therapy, termed CM-YAPon, which triggers YAP activation in CMs upon exposure to a small molecule LMI070. One dose of LMI070 in mice induced a transient expression of active YAP (YAP5SA), which was subsequently degraded within a week. Consistent with earlier findings, YAP activation after injury improved cardiac function. Interestingly, administering a single LMI070 injection two weeks before MI provided lasting cardioprotection, which diminished by four weeks after the transient YAP activation, by reducing non-CMs cell death and enhancing cardiac function. Taken together, our novel gene therapy CM-YAPon presents a promising avenue for developing protective strategies against MI-induced cardiac injury.
2025-09-30 | GSE270256 | GEO
Project description:Myocardial infarction (MI), which affects about 3 million people globally each year, permanently damages the heart and reduces cardiac function1. Recent studies have indicated that activating YAP in cardiomyocytes (CMs) promotes cardiac regeneration and mitigates pathological remodeling in mouse and pig MI models2,3. To precisely control YAP activity in vivo and encourage its clinical application, we developed an adeno-associated virus 9 (AAV9)-based therapy, termed CM-YAPon, which triggers YAP activation in CMs upon exposure to a small molecule LMI070. One dose of LMI070 in mice induced a transient expression of active YAP (YAP5SA), which was subsequently degraded within a week. Consistent with earlier findings, YAP activation after injury improved cardiac function. Interestingly, administering a single LMI070 injection two weeks before MI provided lasting cardioprotection, which diminished by four weeks after the transient YAP activation, by reducing non-CMs cell death and enhancing cardiac function. Taken together, our novel gene therapy CM-YAPon presents a promising avenue for developing protective strategies against MI-induced cardiac injury.
2025-09-30 | GSE293209 | GEO
Project description:Myocardial infarction (MI), which affects about 3 million people globally each year, permanently damages the heart and reduces cardiac function1. Recent studies have indicated that activating YAP in cardiomyocytes (CMs) promotes cardiac regeneration and mitigates pathological remodeling in mouse and pig MI models2,3. To precisely control YAP activity in vivo and encourage its clinical application, we developed an adeno-associated virus 9 (AAV9)-based therapy, termed CM-YAPon, which triggers YAP activation in CMs upon exposure to a small molecule LMI070. One dose of LMI070 in mice induced a transient expression of active YAP (YAP5SA), which was subsequently degraded within a week. Consistent with earlier findings, YAP activation after injury improved cardiac function. Interestingly, administering a single LMI070 injection two weeks before MI provided lasting cardioprotection, which diminished by four weeks after the transient YAP activation, by reducing non-CMs cell death and enhancing cardiac function. Taken together, our novel gene therapy CM-YAPon presents a promising avenue for developing protective strategies against MI-induced cardiac injury.
2025-09-30 | GSE293327 | GEO
Project description:Adverse cardiac remodeling after myocardial infarction (MI) causes structural and functional changes in the heart leading to heart failure. The initial pro-inflammatory response followed by an anti-inflammatory or reparative response post-MI is essential for minimizing the myocardial damage, healing, and scar formation. Bone marrow-derived macrophages (BMDMs) are recruited to the injured myocardium and essential for cardiac repair as they can adopt both pro-inflammatory (M1) or anti-inflammatory/reparative (M2) phenotypes to modulate inflammatory and reparative response, respectively. YAP and TAZ are the key mediators of the Hippo signaling pathway and essential for cardiac regeneration and repair. However, their role in macrophage polarization and post-MI inflammation, remodeling, and healing are not well established. Here, we demonstrate that expression of YAP and TAZ is increased in macrophages undergoing M1 or M2 polarization. Genetic deletion of YAP/TAZ leads to impaired M1 polarization and enhanced M2 polarization. Consistently, YAP activation/overexpression enhanced M1 and impaired M2 polarization. We show that YAP/TAZ promote M1 polarization by increasing IL6 expression, and impede M2 polarization by decreasing Arg1 expression through interaction with the HDAC3-NCoR1 repressor complex. These changes in macrophages polarization due to YAP/TAZ deletion results in reduced fibrosis, and hypertrophy and increased angiogenesis, leading to improved cardiac function after MI. Also, YAP activation augmented MI-induced cardiac fibrosis and remodeling. In summary, we identify YAP/TAZ as important regulators of macrophage-mediated pro- and anti-inflammatory responses post-MI.
2020-10-02 | GSE158889 | GEO
Project description:Ischemic heart disease (IHD) remains a leading cause of mortality worldwide, often culminating in myocardial infarction (MI) and subsequent heart failure due to adverse fibrotic remodeling of the myocardium. Despite the lack of effective treatments, exercise has emerged as a promising strategy to reduce mortality risk and improve cardiac function post-MI. This study investigates the molecular mechanisms underlying exercise-induced cardioprotection by analyzing changes in several key cardiac cell populations after MI in a murine model. We assessed the effect of exercise preconditioning in mouse MI model through echocardiography, followed by single nuclei RNA-seq of cardiac cells, and validation by microscopy and flow cytometry. Our findings demonstrate that exercise significantly enhances cardiac function post-MI, as evidenced by improved ejection fraction and stroke volume in exercised mice. These improvements are linked to adaptive changes across multiple cardiac cell types. Notably, in infarcted mice, exercise caused a downregulation of cardiomyopathy-associated pathways, accompanied by changes in ECs, macrophages, fibroblasts and cardiomyocytes. Exercise stimulated formation of new capillaries which post-MI resulted in a more vascularized infarct border zone. Additionally, exercised hearts displayed a shift in macrophage populations towards a pro-regenerative phenotype, marked by an increase in resident CCR2- macrophages and a reduction in pro-inflammatory M1-gene expression. In cardiomyocytes, exercise enhanced pathways related to endothelial support and ATP biosynthesis, mitigating the upregulation of cardiomyopathy-associated pathways observed post-MI. Importantly, exercise also restored calcium signaling and reversed pathological potassium signaling, thereby preserving contractile function. Fibroblast analysis revealed that exercise stimulated activation of these cells to participate in scar formation. In conclusion, this study provides new insights into the cellular and molecular mechanisms through which exercise enhances cardiac function and provides cardio-protection post-MI, offering potential avenues for targeted therapies in patients with IHD.
2025-09-12 | GSE277123 | GEO
Project description:Sexual dimorphisms are well recognized in various cardiac diseases, including myocardial infarction (MI). MI develops later in women, but once established, it contributes more persistent symptoms and higher mortality than in men. Similar observations have been reported in murine model of MI. Although mRNA-level sexual dimorphism of MI have been reported, whether miRNA transcriptome also confers such dimorphism remains unknown. Comprehensive understanding of the mRNA- and miRNA-level genetic programs underlying the heart sexual dimorphisms will expectedly improve clinical outcome by facilitating the development of gender specific treatment strategies. Here, by conducting miRNA microarray analysis of murine MI model samples, we set out to characterize the heart sexual dimorphisms at the level of miRNA transcriptome The left anterior descending (LAD) coronary artery of mice aged 10 weeks was surgically ligated to create extensive MI. The ventricular septum of the areas at risk of ischemia was sampled on post-operative day 28. Total RNA was extracted using Sepasol solution (Sepasol-RNA I super G, nakalai tesque, Japan), and microarray analysis was performed using Affymetrix GeneChip® miRNA 3.0 Arrays
2016-01-07 | E-GEOD-76592 | biostudies-arrayexpress
Project description:Sexual dimorphisms are well recognized in various cardiac diseases, including myocardial infarction (MI). MI develops later in women, but once established, it contributes more persistent symptoms and higher mortality than in men. Similar observations have been reported in murine model of MI. Although mRNA-level sexual dimorphism of MI have been reported, whether miRNA transcriptome also confers such dimorphism remains unknown. Comprehensive understanding of the mRNA- and miRNA-level genetic programs underlying the heart sexual dimorphisms will expectedly improve clinical outcome by facilitating the development of gender specific treatment strategies. Here, by conducting miRNA microarray analysis of murine MI model samples, we set out to characterize the heart sexual dimorphisms at the level of miRNA transcriptome
2016-01-07 | GSE76592 | GEO
Project description:Cardiac hypertrophy can lead to heart failure, and is induced either by physiological stimuli eg postnatal development, chronic exrcise training or pathological stimuli eg pressure or volume overload. This data set looks at microRNA profiles in mouse models to examine whether phosphoinositide 3-kinase (p110 alpha isoform) activity is critical for the maintenance of cardiac function and long term survival in a seeting of heart failure (myocardial infarction). The significance and expected outcome are to recognise genes involved in models of heart failure and attempt to examine underlying regulator pathways involved in possible cardica maintenance in the PI3K mouse model. The matching mRNA gene expression profile (GSE7487) is examined to look for mRNA and microRNA interactions. miRNA expression correlates directly with cardiac function. PI3K regulon ameliorates cardiac stress. Keywords: microRNA profiling, regulatory pathway discovery, genotype comparison Ntg (non-transgenics), dnPI3K (cardiac-specific transgenic model with reduced PI3K activity) and caPI3K (transgenic mice with increased PI3K activity) mice at 3-4 months of age were used. Mice were then subjected to myocardial infarction (occlusion of the left anterior descending aorta) and sham (open heart surgery) for 8 weeks. Left ventricles were harvested. The resulting 6 experimental models were profiled accordingly. The assignment of the mouse models is as follows: caPI3K Sham, Ntg Sham, dnPI3K Sham, caPI3K MI (myocardial infarction), Ntg MI and dnPI3K MI with n = 4 in each group.
2010-05-06 | E-GEOD-14267 | biostudies-arrayexpress