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TFEB activation in macrophages attenuates postmyocardial infarction ventricular dysfunction independently of ATG5-mediated autophagy

ABSTRACT: TFEB activation in macrophages attenuates postmyocardial infarction ventricular dysfunction independently of ATG5-mediated autophagy

PROVIDER: PRJNA485726 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7688350.fastq.gz	Fastqsanger.gz
	SRR7688360.fastq.gz	Fastqsanger.gz
	SRR7688370.fastq.gz	Fastqsanger.gz
	SRR7688351.fastq.gz	Fastqsanger.gz
	SRR7688361.fastq.gz	Fastqsanger.gz

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TFEB activation in macrophages attenuates postmyocardial infarction ventricular dysfunction independently of ATG5-mediated autophagy

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

TFEB activation in macrophages attenuates postmyocardial infarction ventricular dysfunction independently of ATG5-mediated autophagy.

Project description:Lysosomes are at the epicenter of cellular processes critical for inflammasome activation in macrophages. Inflammasome activation and IL-1β secretion are implicated in myocardial infarction (MI) and resultant heart failure; however, little is known about how macrophage lysosomes regulate these processes. In mice subjected to cardiac ischemia/reperfusion (IR) injury and humans with ischemic cardiomyopathy, we observed evidence of lysosomal impairment in macrophages. Inducible macrophage-specific overexpression of transcription factor EB (TFEB), a master regulator of lysosome biogenesis (Mϕ-TFEB), attenuated postinfarction remodeling, decreased abundance of proinflammatory macrophages, and reduced levels of myocardial IL-1β compared with controls. Surprisingly, neither inflammasome suppression nor Mϕ-TFEB-mediated attenuation of postinfarction myocardial dysfunction required intact ATG5-dependent macroautophagy (hereafter termed "autophagy"). RNA-seq of flow-sorted macrophages postinfarction revealed that Mϕ-TFEB upregulated key targets involved in lysosomal lipid metabolism. Specifically, inhibition of the TFEB target, lysosomal acid lipase, in vivo abrogated the beneficial effect of Mϕ-TFEB on postinfarction ventricular function. Thus, TFEB reprograms macrophage lysosomal lipid metabolism to attenuate remodeling after IR, suggesting an alternative paradigm whereby lysosome function affects inflammation.

| S-EPMC6948771 | biostudies-literature

Mitochondrial Ferritin Inhibition Aggravates Pacing-induced Ventricular Arrhythmias after Myocardial Infarction by Promoting Cardiomyocytes Ferroptosis

Project description:Our findings suggest that FtMt serves as a protective function in myocardial infarction by limiting infarct size, reducing the incidence of ventricular arrhythmias, and inhibiting ferroptosis both in vivo and in vitro. Our results also indicate that FtMt could be a promising therapeutic target for myocardial infarction.

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Identification of TFEB regulated genes during in vitro RGC to EPC differentiation (RNA-seq)

Project description:The largest germinal niche of the adult mammal brain locates at the ventricular zone (VZ), which is made up of adult neural stem cells (NSCs) and multiciliated ependymal cells (EPCs). Both NSCs and EPCs derive from radial glia (RG), whereas the transcriptomic dynamic changes of the cell fate continuum remain elusive. Here, we identified a key transcription factor TFEB that is important during EPC differentiation. We knockdown TFEB using siRNA and check gene expression changes upon TFEB depletion by RNA-seq.

2024-04-21 | E-MTAB-13856 | biostudies-arrayexpress

TFEB degradation is regulated by an IKK/TrCP2 phosphorylation-ubiquitination cascade

Project description:IKK/beta-TrCP2 phosphorylation-ubiquitination cascade as a major mechanism that governs TFEB stability independently of other TFEB regulators.

2024-07-17 | MSV000095363 | MassIVE

Experimentally induced myocardial infarction in mice - RNA Sequencing of sham left ventricular tissue and infarct zones

Project description:To induce myocardial infarction, ligation of left anterior descending (LAD) coronary artery was performed for 5d. After 5d heart tisse was collected from the infarct zone of MI-mice and left ventricular tissue of sham operated mice.

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To identify differentially expressed genes in ventricular tissue between wildtype control and the 6-month-old mtorxu015/+ mutant, Tg(cmlc2:tfeb) transgenic zebrafish at six months.

Project description:To seek molecular mechanisms underlying the mechanisms of mutant genotypes by comparing them witht he wild types, we performed whole transcriptome RNA-sequencing experiments using ventricular tissue isolated from 6-month-old mtorxu015/+ mutant, Tg(cmlc2:tfeb) transgenic zebrafish,and corresponding WT siblings.

2025-06-12 | GSE269725 | GEO

Transcription profiling of human left ventricular apex samples

Project description:19 paired human left ventricular apex samples were harvested at the time of implant of a left ventricular assist device (PRE) and at the time of explant (POST). The cohort included patients that were clinically classified as ischemic (I) showing evidence of coronary artery disease, non-ischemic (N) no evidence of coronary artery disease or acute Myocardial infarction (IM) myocardial infarction within 10 days of the implant. Tissue was processed and hybridized to the Affymetrix HG-U133A chip.

2007-10-02 | E-GEOD-974 | biostudies-arrayexpress

Left ventricular apex samples

Project description:19 paired human left ventricular apex samples were harvested at the time of implant of a left ventricular assist device (PRE) and at the time of explant (POST). The cohort included patients that were clinically classified as "ischemic" (I) showing evidence of coronary artery disease, "non-ischemic" (N) no evidence of coronary artery disease or "acute Myocardial infarction" (IM) myocardial infarction within 10 days of the implant. Tissue was processed and hybridized to the Affymetrix HG-U133A chip. Keywords: other

2004-01-18 | GSE974 | GEO

Plasma circulating extracellular RNAs in left ventricular remodeling post-myocardial infarction

Project description:Plasma circulating extracellular RNAs in left ventricular remodeling post-myocardial infarction

| PRJNA448747 | ENA