Effect of Card9 knockout on gene expression in cardiac tissues of mice post myocardial infarction
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE235257 | GEO | 2023/10/25
REPOSITORIES: GEO
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Project description:Myocardial infarction (MI) results from occlusion of blood supply to the heart muscle causing death of cardiac muscle cells. Following myocardial infarction (MI), scar formation acts to mechanically stabilise the injured heart to prevent rupture and death. While fibroblasts and macrophages are implicated in post-MI scar formation and maturation, their exact contributions to this process are poorly characterised, especially in the long-term (i.e., beyond 1-week post-MI). Here, we employ state-of-the-art spatially-targetted optical micro-proteomics (STOMP) to isolate proteomes of tissue fractions enriched for fibroblasts (sma+) and macrophages (cd68+) over a 6-week post-MI timecourse and compare them to whole-scar proteome. We illustrate dynamic, specific changes in sma- and cd68-enriched fraction protein composition over 1-6 weeks post-MI with some of these changes reflected in whole-infarct preparations. These results link specific cell populations to specific protein changes in whole infarct.
2023-10-31 | PXD034413 | Pride
Project description:Myocardial infarction (MI) is a highly prevalent cardiac emergency, which results in adverse left ventricular remodeling exacerbating progressive heart failure. Inflammation in post-MI is necessary for myocyte repair and wound healing. However, it is also a key component of subsequent heart failure pathology. Myoblasts transplantation after MI have been fulfilled a good effect on cardiac repair, but the occasion, complications of transplantation, and the underlying mechanisms have not been fully elucidated. Here, we found that myoblast transplantation decreased the expression of many pro-inflammatory genes and the activation of inflammation-related signal pathway in heart tissue of pig post MI, which mainly contributed to the improved heart function and attenuated damage of myocardial cells.
2017-01-28 | GSE94151 | GEO
Project description:Background: The adult mammalian heart has limited ability to repair itself following injury. Zebrafish, newts and neonatal mice can regenerate cardiac tissue, largely by cardiac myocyte (CM) proliferation. It is unknown if hearts of young large mammals can regenerate. Methods: We examined the regenerative capacity of the pig heart in neonatal animals (ages: 2, 3 or 14 days postnatal) after myocardial infarction (MI) or sham procedure. Myocardial scar and left ventricular function were determined by cardiac magnetic resonance (CMR) imaging and echocardiography. Bromodeoxyuridine pulse-chase labeling, histology, immunohistochemistry and Western blotting were performed to study cell proliferation, sarcomere dynamics and cytokinesis and to quantify myocardial fibrosis. RNA-sequencing was also performed. Results: After MI, there was early and sustained recovery of cardiac function and wall thickness in the absence of fibrosis in 2-day old pigs. In contrast, older animals developed full-thickness myocardial scarring, thinned walls and did not recover function. Genome wide analyses of the infarct zone revealed a strong transcriptional signature of fibrosis in 14-day old animals that was absent in 2-day old pigs, which instead had enrichment for cytokinesis genes. In regenerating hearts of the younger animals, up to 10% of CMs in the border zone of the MI showed evidence of DNA replication that was associated with markers of myocyte division and sarcomere disassembly. Conclusions: Hearts of large mammals have regenerative capacity, likely driven by cardiac myocyte division, but this potential is lost immediately after birth.
2018-09-12 | GSE115665 | GEO
Project description:Myocardial infarction (MI) contributes to cardiac mortality and morbidity. After myocardial infarction the innate immune response is pivotal in clearing of tissue debris as well as scar formation, but exaggerated cytokine and chemokine secretion with subsequent leukocyte infiltration also leads to further tissue damage. Post-translational regulation of cytokine / chemokine signaling occurs via ectodomain shedding through a disintegrin and metalloproteases (ADAMs). Here, we address the value of targeting a previously unknown ADAM10 / CX3CL1 axis in the regulation of neutrophil recruitment early after MI. We show that myocardial ADAM10 is distinctly upregulated in biopsies from patients with ischemia-driven cardiomyopathy and correlates with heart failure progression. Intriguingly, upon MI in mice, pharmacological treatment with the ADAM10 inhibitionor GI254023X as well as genetic cardiomycyte-specific ADAM10 deletion improves survival with markedly enhanced heart function and reduced scar size. Mechanistically, this is driven by abolished ADAM10-mediated CX3CL1 ectodomain shedding followed by diminished IL-1β-dependent inflammation, reduced neutrophil bone marrow egress as well as myocardial tissue infiltration. Genetic cardiomycyte-specific ADAM10 deletion confirmes the small-molecule data and leads to improved cardiac function and reduction in inflammatory markers after ischemic myocardial injury. Thus, our data shows a conceptual insight into how acute MI induces chemotactic signaling via ectodomain shedding in cardiomyocytes.
2022-11-10 | GSE217268 | GEO
Project description:Fibrotic scarring drives the progression of heart failure after myocardial infarction (MI). Therefore, the development of specific treatment regimens to counteract fibrosis is of high clinical relevance. The transcription factor SOX9 functions as an important regulator during embryogenesis, but recent data point towards an additional causal role in organ fibrosis. We show here that SOX9 is upregulated in the scar after MI in mice. Fibroblast specific deletion of Sox9 ameliorated MI-induced left ventricular dysfunction, dilatation and myocardial scarring in vivo. Unexpectedly, deletion of Sox9 also potently eliminated persisting leukocyte infiltration of the scar in the chronic phase after MI. RNA-sequencing from the infarct scar revealed that Sox9 deletion in fibroblasts resulted in strongly downregulated expression of genes related to extracellular matrix, proteolysis and inflammation. Importantly, Sox9 deletion in isolated cardiac fibroblasts in vitro similarly affected gene expression as in the cardiac scar and prevented their activation and myofibroblast differentiation. Together, our data demonstrate that fibroblast SOX9 functions as a master regulator of cardiac fibrosis and inflammation and might constitute a novel therapeutic target during MI.
2019-07-25 | GSE132265 | GEO
Project description:The aims of the experiment were to profile the cell types in the adult mouse cardiac interstitium (non-myocyte cells) and how they respond to myocardial infarction injury. Adult, male, Pdgfra +/GFP mice were subject to either a myocardial infarction or sham injury, with cells isolated from cardiac ventricles 3 or 7 days following surgery. We obtained scRNA-seq profiles of two cell fractions: total interstitial (non-myocyte) cell population (TIP) and FACS-sorted GFP+/Cd31- cells (GFP).
2019-03-28 | E-MTAB-7376 | biostudies-arrayexpress
Project description:Heart failure (HF) is a leading cause of morbidity and mortality. As adult cardiomyocytes (CMs) have little regenerative capacity, after myocardial infarction (MI), resident cardiac fibroblasts (CFs) synthesize extracellular matrix to form scar tissues, resulting in myocardial remodeling and HF. Thus, both cardiac regeneration and fibrosis are therapeutic targets for chronic MI. We previously reported that fibroblasts were directly reprogrammed into induced CMs (iCMs) by overexpression of cardiogenic transcription factors in vitro and in vivo in acute MI. Here we show that in vivo cardiac reprogramming generated iCMs from resident CFs, improved cardiac function, and reversed fibrosis in chronic MI using a novel transgenic mouse system. Transcriptome analysis revealed that in vivo cardiac reprogramming altered the interstitial cell landscape, suppressed signs of fibrosis and inflammation, and activated the angiogenic program. Thus, in vivo cardiac reprogramming may be a promising approach for chronic HF.
2022-12-12 | GSE183932 | GEO
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:Heart failure (HF) is a leading cause of morbidity and mortality. As adult cardiomyocytes (CMs) have little regenerative capacity, after myocardial infarction (MI), resident cardiac fibroblasts (CFs) synthesize extracellular matrix to form scar tissues, resulting in myocardial remodeling and HF. Thus, both cardiac regeneration and fibrosis are therapeutic targets for chronic MI. We previously reported that fibroblasts were directly reprogrammed into induced CMs (iCMs) by overexpression of cardiogenic transcription factors in vitro and in vivo in acute MI. Here we show that in vivo cardiac reprogramming generated iCMs from resident CFs, improved cardiac function, and reversed fibrosis in chronic MI using a novel transgenic mouse system. Single-cell transcriptome analysis revealed that cardiac reprogramming shifted matrix-producing CFs, matrifibrocytes, to a quiescent state and changed the interstitial cell landscape, suppressing fibrotic and inflammatory signatures and activating angiogenic program. Thus, in vivo cardiac reprogramming may be a promising approach for chronic HF.
2022-12-12 | GSE185265 | GEO
Project description:Prognosis after myocardial infarction (MI) varies greatly depending of the extent of damaged area and the management of biological processes during recovery. Reportedly, the inhibition of the pro-inflammatory S100A9 reduces myocardial damage after MI. We hypothesize that S100A9 blockade induces changes of major signaling pathways implicated in post-MI healing. The S100A9 blocker (ABR-23890) was given for 3 days after coronary ligation. At 3- and 7-days post-MI, ventricle samples were analyzed versus control and sham-operated mice. Blockade of S100A9 modulated the expressed proteins involved in five biological processes: leu-kocyte cell-cell adhesion, regulation of muscle cell apoptotic process, regulation of intrinsic apoptotic signaling pathway, sarcomere organization and cardiac muscle hypertrophy. The blocker induced regulation of 36 proteins interacting with or targeted by the cellular tumor antigen p53, prevented myocardial compensatory hypertrophy, and reduced cardiac markers of post-ischemic stress. The blockade effect was prominent at day 7 post-MI when the quantitative features of ventricle proteome were closer to controls.
2022-05-19 | PXD033683 | Pride