ATF3 coordinates the survival/proliferation of cardiac macrophages to protect against ischemia-reperfusion injury
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE247139 | GEO | 2023/11/07
REPOSITORIES: GEO
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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:To determine the mechanism by which ATF3 regulated the survival/proliferation of MerTK+ cardiac macrophages, microarray was performed to identify gene expression differences in MerTK+ macrophages from WT and ATF3-CKO mice under the HR state.
2023-10-31 | GSE246338 | GEO
Project description:Lysosomes are at the epicenter of cellular processes critical for inflammasome activation in macrophages, including autophagy and lipid metabolism. Inflammasome activation and IL1-beta secretion are implicated in atherogenesis, ischemic cardiac injury and resultant heart failure; however, little is known about the role of macrophage lysosome function in regulating these processes. We hypothesized that macrophages exhibit lysosome dysfunction in heart failure due to ischemic injury, and that augmentation of macrophage lysosomal biogenesis via macrophage-specific overexpression of transcription factor EB (mf-TFEB) would attenuate ischemic remodeling by modulating macrophage inflammatory responses. In both mice subject to ischemia-reperfusion injury, and human heart tissue from patients with ischemic cardiomyopathy, we find evidence of lysosome insufficiency and autophagic impairment, respectively. Mf-TFEB overexpression significantly attenuated post-IR adverse left ventricular remodeling at 4 weeks without affecting scar size. Mf-TFEB overexpression reduced the relative amounts of pro-inflammatory macrophage populations in the myocardium. RNA sequencing of flow-sorted cardiac macrophages post-IR confirmed that TFEB stimulated a lysosomal transcriptional program in macrophages, and upregulated key targets involved in lysosomal lipid metabolism, which we show are critical for inflammasome suppression. Both TFEB-dependent inflammasome suppression and effects on post-IR remodeling were independent of autophagy. Our findings suggest that TFEB reprograms macrophage lysosomal lipid metabolism to attenuate inflammasome activity and protect against post-ischemic cardiac remodeling and simultaneously shift our understanding of how autophagy and lipid metabolism impact acute inflammation.
2019-11-01 | GSE118463 | 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: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: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.
2012-01-31 | GSE35421 | 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:Mononuclear phagocytes promote injury and repair following myocardial infarction but discriminating functions within mixed populations remains challenging. We utilized fate mapping and single cell RNA-sequencing to delineate fate specification trajectories of heterogeneous cardiac macrophage subpopulations. In steady state, TIMD4 expression tracked with a dominant resident cardiac macrophage subset that persisted via in situ self-renewal with minimal monocyte input. Following ischemic injury, monocytes displayed significant plasticity, ultimately adopting transcriptional states similar to resident macrophages, but also multiple unique states. Ischemic injury reduced resident macrophage abundance within infarct tissue, and despite transcriptional similarity, TIMD4 expression distinguished resident from recruited macrophages. Specific lineage-based depletion of resident cardiac macrophages resulted in depressed cardiac function and adverse remodeling primarily within the peri-infarct zone, the only region of the myocardium where resident macrophages expanded numerically following injury. Together, these data highlight a non-redundant, cardioprotective role of resident cardiac macrophages, and the diverse transcriptional fates recruited monocytes can adopt.
2018-12-15 | GSE119355 | GEO
Project description:Adult mammalian hearts do not regenerate following ischemic injury, causing permanent damage to the myocardium, often leading to heart failure. In contrast, neonatal mouse hearts can fully regenerate after injury, however this ability is lost shortly after birth. Loss of regenerative capacity coincides with profound changes in the epigenetic landscape. Yet, the mechanisms controlling cardiomyocyte proliferation remain poorly understood. To identify epigenetic mechanisms that underlie cardiomyocyte regeneration in response to ischemic injury, we subjected mice to sham or ischemia-reperfusion injury (IR) and performed RNA-Seq at multiple timepoints after injury. Multiple SWI/SNF chromatin remodeling complex subunits were upregulated after IR, including the AT-rich interactive domain-containing protein 1A (Arid1a), which has previously been implicated in tissue regeneration. Here, we show that Arid1a is abundantly expressed in cardiomyocytes during development, and is reactivated in a subset of adult cardiomyocytes after IR. Moreover, ARID1A is highly expressed in cardiomyocytes in human failing hearts, suggesting an important function in injury response. Cardiomyocyte-specific Arid1a ablation in neonatal mice induced cardiomyocyte hyperplasia, and severe cardiac enlargement at 2 weeks of age. Arid1a mutant hearts display increased expression of key cell cycle genes. Using ChIP-Seq and protein interaction studies we show that Arid1a functionally interacts with HIPPO signaling, thereby regulating neonatal cardiomyocyte proliferation. Furthermore, suppression of Arid1a in adult cardiomyocytes after IR induced cell cycle activity in border zone cardiomyocytes. These data suggest that Arid1a regulates cardiomyocyte proliferation and function. Upregulation of Arid1a in cardiomyocytes after injury may suppress proliferation and regeneration. Modulation of ARID1A after ischemic injury may be a novel therapeutic target to enhance cardiac regeneration.
2023-07-06 | GSE155100 | GEO
Project description:Adult mammalian hearts do not regenerate following ischemic injury, causing permanent damage to the myocardium, often leading to heart failure. In contrast, neonatal mouse hearts can fully regenerate after injury, however this ability is lost shortly after birth. Loss of regenerative capacity coincides with profound changes in the epigenetic landscape. Yet, the mechanisms controlling cardiomyocyte proliferation remain poorly understood. To identify epigenetic mechanisms that underlie cardiomyocyte regeneration in response to ischemic injury, we subjected mice to sham or ischemia-reperfusion injury (IR) and performed RNA-Seq at multiple timepoints after injury. Multiple SWI/SNF chromatin remodeling complex subunits were upregulated after IR, including the AT-rich interactive domain-containing protein 1A (Arid1a), which has previously been implicated in tissue regeneration. Here, we show that Arid1a is abundantly expressed in cardiomyocytes during development, and is reactivated in a subset of adult cardiomyocytes after IR. Moreover, ARID1A is highly expressed in cardiomyocytes in human failing hearts, suggesting an important function in injury response. Cardiomyocyte-specific Arid1a ablation in neonatal mice induced cardiomyocyte hyperplasia, and severe cardiac enlargement at 2 weeks of age. Arid1a mutant hearts display increased expression of key cell cycle genes. Using ChIP-Seq and protein interaction studies we show that Arid1a functionally interacts with HIPPO signaling, thereby regulating neonatal cardiomyocyte proliferation. Furthermore, suppression of Arid1a in adult cardiomyocytes after IR induced cell cycle activity in border zone cardiomyocytes. These data suggest that Arid1a regulates cardiomyocyte proliferation and function. Upregulation of Arid1a in cardiomyocytes after injury may suppress proliferation and regeneration. Modulation of ARID1A after ischemic injury may be a novel therapeutic target to enhance cardiac regeneration.
2023-07-06 | GSE155101 | GEO