Genome-wide analysis of gene expression changes in miR-214 KO mouse hearts and skeletal muscle
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE35421 | GEO | 2012/01/31
SECONDARY ACCESSION(S): PRJNA152583
REPOSITORIES: GEO
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Project description:Early reperfusion of ischemic cardiac tissue remains the most effective intervention for improving clinical outcome following myocardial infarction. However, abrupt increases in intracellular Ca2+ during myocardial reperfusion cause cardiomyocyte death and consequent loss of cardiac function, referred to as ischemia/reperfusion (IR) injury. Cardiac IR is accompanied by dynamic changes in expression of microRNAs (miRNAs), which inhibit specific mRNA targets. miR-214 is up-regulated during ischemic injury and heart failure in mice and humans, but its potential role in these processes is unknown. We show that genetic deletion of miR-214 in mice causes loss of cardiac contractility, increased apoptosis, and excessive fibrosis in response to IR injury. The microarray contains 6 samples, each containing cDNA pooled from 3 mice per group. There are no replicates. The array was designed to make 3 different pairwise comparisons between the following: P14 WT and miR-214 KO hearts; adult WT and miR-214 KO skeletal muscle; adult WT and miR-214 KO hearts
2012-01-31 | E-GEOD-35421 | biostudies-arrayexpress
Project description:Cardiac resident MerTK+ macrophages exert multiple protective roles post-ischemic injury. To determine the potential reason for the protective role of MerTK+ cardiac macrophages, microarray was performed to identify gene expression profiles on isolated Trem2+, MHCII+, Lyve1+, and MerTK- macrophages from the heart tissue of WT mice post-IR. We investigated the potential reason for the protective role of MerTK+ cardiac macrophages in myocardial Ischemia reperfusion injuryby microarray.
2023-10-31 | GSE246339 | GEO
Project description:This study was a part of a larger study assessing the response of young pigs to cardiac ischemia/reperfusion (IR) injury. A mild cardiac injury approach (IR) was used in post-weaned pigs (1-month), to assess regenerative repair in young large mammals after transient ischemic injury. Female and male postnatal day (P)30 pigs were subjected to cardiac ischemia (1-hour) by occlusion of the left anterior descending artery followed by reperfusion (IR), or to sham operation. In pigs subjected to IR, myocardial damage occurred, indicated by increased circulating cardiac troponin I 2-hours post-ischemia. In addition, cardiac ejection fraction (EF) was significantly decreased 2-hours post-ischemia and reduced EF was maintained to the 4-week study end-point. Histology demonstrated evidence of CM cell cycling at 2-months of age in multinucleated CMs in both sham-operated and IR pigs. Following IR, regional scar formation and inflammation in the epicardial region proximal to injury were observed 4-weeks post-IR. Sex differences in cardiac function and collagen deposition were found, highlighting the importance of representing both sexes in cardiac injury studies. Together, our results describe an effective novel cardiac injury model in 1-month old swine, at a time when CM are still cycling. However, pigs subjected to IR show a prolonged decrease in cardiac function, and the formation of a small, regional scar with increased inflammation. Together, these data demonstrate that 1-month old pigs do not regenerate myocardium, but form a scar, after transient IR injury.
2020-04-27 | GSE137293 | GEO
Project description:Coronary heart disease is the leading cause of death worldwide. After an acute myocardial infarction, early reperfusion reduces infarct size, which correlates with improved clinical outcomes. Paradoxically, reperfusion although relieving ischemia, accelerates apoptosis in injured cardiomyocytes, which has led to the view that myocardial salvage is futile beyond the first few hours of reperfusion. In murine hearts subjected to 90 min of coronary artery occlusion and then 48 h of reperfusion, we show transient activation of intrinsic prosurvival insulin-like growth factor-1 (IGF-1) signaling. In these hearts, acute IGF-1 receptor inhibition decreases the abundance of prosurvival signaling molecules, and markedly activates caspase-3, a potent effector of apoptosis, in infarct border zone cardiomyocytes. We found that mouse mast cell protease-4 (MMCP-4) degraded IGF-1 in vitro by a novel catalytic activity of chymases. In vivo, this degradation, which is triggered by mast cell infiltration into the peri-infarct region and MMCP-4 extravasation, between 48 and 72 h post-ischemia/reperfusion (I/R), attenuates IGF-1 prosurvival signaling. In MMCP-4-deficient mice, while infarct size is not reduced at 24 h post-I/R, at 72 h post-I/R myocardial IGF-1 levels and signaling are increased, resulting in activation of the survival kinases Akt and ERK, inhibition of caspase-3, and reduced myocardial cell death. As a consequence, I/R-mediated loss of viable myocardium, adverse cardiac remodeling and contractile impairment are markedly reduced. Cardiomyocyte survival with consequent myocardial salvage may thus be possible even days after an ischemic insult, making them a novel therapeutic target for delayed cardioprotective therapy. Group 1 is wild type C57Bl6 uninjured hearts. These mice were not undergone any surgery and used as controls. Group 2 are wild type C57Bl6 72 h post-ischemia reperfusion (IR) injury hearts. These mice for subjected to ischemia reperfusion (IR) involving 90 min of left anterior descending coronary artery occlusion followed by reperfusion for 3 days or 72 h.
2015-09-01 | E-GEOD-61592 | biostudies-arrayexpress
Project description:Cardiac resident MerTK+ macrophages exert multiple protective roles post-ischemic injury, however, the mechanisms regulating their fate are not fully understood. Here we show that GAS6-inducible transcription factor ATF3 prevents apoptosis of MerTK+ macrophages after ischemia-reperfusion (IR) injury, by repressing the transcription of multiple genes involved in type I interferon expression (Ifih1 and Infb1) and apoptosis (Apaf1). Mice lacking ATF3 in cardiac macrophages or myeloid cells showed excessive loss of MerTK+ cardiac macrophages, poor angiogenesis, and worse heart dysfunction post-IR, which were rescued by the transfer of MerTK+ cardiac macrophages. GAS6 administration improved cardiac repair in an ATF3-dependent manner. Finally, we showed a negative association of GAS6 and ATF3 expression with the risk of major adverse cardiac events in patients with ischemic heart disease. These results indicate that the GAS6-ATF3 axis has a protective role against IR injury by regulating MerTK+ cardiac macrophage survival/proliferation.
2023-11-07 | GSE247139 | GEO
Project description:The management of cardiac ischemic injury has been challenged by ischemia and reperfusion (I/R) injury. Reactive oxygen species (ROS) generated from mitochondrial reverse electron transport (RET) during the early phase of reperfusion is considered to be the initiating cause for ischemia and reperfusion injury. Ginsenosides and their prescriptions are widely used in the clinic for treatment of myocardial ischemia, however, the action to combat ROS remains to be elucidated. In this work, we used TMT-based proteomic approach to detect differential proteins from mitochondrial fractions of mice hearts with ischemia-reperfusion. Results indicated that the mass error of identified peptides was within 10 ppm, and most of the identified peptides were composed of 7-23 amino acids. Using these qualified data, 17,262 peptides, with a confidence level ≥ 95%, were mapped to 3,054 protein groups. PCA analysis showed that the model group was clearly separated from the blank group, while the protein pattern was partly reversed with Rb1 treatment. With a criteria of p-value < 0.05, 591 significantly changed proteins including 186 increased and 405 decreased ones in the model group were identified compared with the blank group. These proteins were divided into 4 clusters. Proteins in Cluster I highly increased in the model group, but clearly decreased in the Rb1 group. Proteins in Cluster IV clearly decreased in the model group, but markedly increased in the Rb1 group. Proteins in Cluster III and in Cluster IV were not significantly or slightly regulated by the Rb1 treatment. GO analysis of Cluster I and II indicated that the molecular function of these proteins were closely related to oxidoreductase activity and NADH dehydrogenase activity. Our result showed that Rb1 administration before ischemia markedly decreased infarct size (48 h post-I/R), and preserved cardiac function (2 weeks post-I/R), and subsequently limited tissue fibrosis (28 days post-I/R). These results indicated that targeted inhibition of mitochondrial complex I in the early stage of reperfusion by Rb1 is a potential therapeutic strategy for alleviating IR injury. This work not only indicates a potent molecular target for the precision therapy of myocardial ischemia by Rb1, but also provides novel knowledge for the management of cardiac ischemic injury by traditional Chinese medicine.
2021-09-08 | PXD011414 | Pride
Project description:Background: Acute kidney injury (AKI) is a common clinical event with high morbidity and mortality. We previously demonstrated that injection of cord blood endothelial colony forming cell (ECFC)-derived exosomes, highly enriched in miRNA(miR)-486-5p, prevented ischemic kidney injury in mice. While preclinical models support involvement of several miRs in AKI, the direct effects of miR-486-5p on injury and the kidney transcriptome are unknown. Objective: We studied effects of miR-486-5p in mice with kidney ischemia-reperfusion (IR) injury, and compared the impact of miR-486-5p and ECFC-derived exosomes on the transcriptome of proximal tubules (PTs) and renal endothelial cells. Methods: Adult male mice were subjected to bilateral kidney ischemia (30 min), and injected via tail vein with or without vehicle, miR-486-5p mimic, ECFC-derived exosomes, or scramble miR at the start of reperfusion. Plasma and tissues were collected 24 hrs after reperfusion, and proximal tubular and endothelial cells were isolated for mRNA analysis by RNA-Seq. Results: In mice with kidney IR, injection of miR-486-5p mimic increased levels of miR-486-5p in proximal tubules and endothelial cells, and significantly improved plasma creatinine, histological injury, neutrophil infiltration, and apoptosis, compared to vehicle treatment. MiR-486-5p inhibited expression of phosphatase and tensin homolog (PTEN), and activated AKT. Similar results were observed with exosomes, but scramble miR had no effect. In proximal tubules, miR-486-5p or exosomes reduced expression of several AKI genes (e.g. Lcn2, Havcr1 and Krt20) and caused alterations in apoptotic genes compared to IR alone. In endothelium, miR-486-5p or exosomes caused milder effect than in PTs but still impacting on expression of injury-related genes. Conclusion: MiR-486-5p protects mice against ischemic kidney injury. Both miR-486-5p and exosomes reduce expression of apoptotic genes in PTs and endothelium. The results suggest that systemic delivery of miR-486-5p has therapeutic potential in ischemic AKI.
2023-10-10 | GSE159701 | GEO
Project description:Ischemia-reperfusion (IR) injury, a ubiquitous consequence of liver transplantation, is a cause of early graft rejection and increased morbidity. At present, there are no effective strategies to reduce hepatic IR injury. Molecular mechanisms that promote cell survival under these circumstances are largely undefined. We examined changes in global gene expression at early reperfusion times to identify potential IR-mediated protective responses. Using a rat model of 30 minutes of 70% warm ischemia followed by reperfusion, RNA for microarray analysis was extracted from the non-ischemic and the ischemic-reperfused lobes at four reperfusion times: 0 (no reperfusion), 0.5, 2, and 6 hours. Differentially expressed genes and pathway analyses were used to identify IR-induced events. The transcriptome of the reperfused lobes was unique and discrete at each reperfusion time, showing no evidence of sustained changes of the gene expression alterations seen at 30 minutes of reperfusion. At all reperfusion times, a significant portion of gene expression changes in the reperfused lobes were present in the non-ischemic lobes. However, the earliest reperfusion time, 30 minutes, showed a marked increase in the expression of a set of immediate-early genes (c-Fos, c-Jun, Atf3, Egr1) that was exclusive to the reperfused lobe. Similarities of gene expression changes in the reperfused and the non-ischemic lobes at each time suggest that hemodynamics and/or circulating factors are potent stimuli in an IR model. However, early reperfusion events appear to reflect a cell-autonomous response that may be protective, thereby representing potential targets to ameliorate IR injury.
2019-12-16 | GSE117915 | GEO
Project description:In this study, we examined if KLF4 and c-MYC (KM)-transduced murine cardiac mesenchymal progenitors (CMPs) played a role in the differentiation into adipocytes in the absence of adipogenic stimulation cocktails. These progenitors exhibited increased expression of adipogenic-related genes, such as C/EBPα, PPARγ, and Fabp4, activation of the PPAR signaling pathway, and formation of cytoplasmic lipid droplets within 10 days. Moreover, these KM genes sharply increased following a reperfusion insult, resulting in increased ectopic fat formation. Thus, understanding CMP adipogenesis will clarify the pathophysiology of ischemic reperfusion injury and myocardial infarction and may pave the way for better treatment strategies. Adult mouse cardiac mesenchymal progenitor cells were treated with OSKM for 0, 4, 6, or 8 days.
2015-09-01 | E-GEOD-70088 | biostudies-arrayexpress
Project description:Aims: Mesenchymal stem cells (MSCs) gradually become attractive candidates for cardiac inflammation modulation, yet understanding of the mechanism remains elusive. Strikingly, recent studies indicated that exosomes secreted by MSCs might be a novel mechanism for the beneficial effect of MSCs transplantation after myocardial infarction. We therefore explored the role of MSC-derived exosomes (MSC-Exo) in the immunomodulation of macrophages after myocardial ischemia-reperfusion and its implications in cardiac injury repair. Methods and Results: Exosomes were isolated from the supernatant of MSCs using a gradient centrifugation method. Administration of MSC-Exo through intramyocardial injection after myocardial ischemia reperfusion reduced infarct size and alleviated inflammation level in heart and serum. Systemic depletion of macrophages with clodronate liposomes abolished the curative effects of MSC-Exo. MSC-Exo modified the polarization of M1 macrophages to M2 macrophages both in vivo and in vitro. miRNA-sequencing of MSC-Exo and bioinformatics analysis implicated miR-182 as a potent candidate mediator of macrophage polarization and TLR4 as a downstream target. Diminishing miR-182 in MSC-Exo partially attenuated its modulation of macrophage polarization. Likewise, knock down of TLR4 also conferred cardioprotective efficacy and reduced inflammation level in a mouse model of myocardial ischemia/reperfusion. Conclusion: Our data indicates that MSC-Exo attenuates myocardial ischemia/reperfusion injury via shuttling miR-182 that modifies the polarization state of macrophages. This study sheds new light on the application of MSC-Exo a potential therapeutic tool for myocardial ischemia/reperfusion injury.
2021-09-01 | GSE120149 | GEO