Macrophage MERTK mediates pressure overload-induced heart failure via type I interferon response
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ABSTRACT:
PROVIDER: PRJNA1311097 | ENA |
REPOSITORIES: ENA
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Project description:Macrophages play a critical role in the pathogenesis and progression of heart failure, wherein sustained cardiomyocyte apoptosis is a key feature. The MER proto-oncogene tyrosine kinase (MERTK) is a critical receptor that mediates the efferocytosis of apoptotic cells by macrophages. However, the role and mechanism of action of MERTK in pressure overload-induced heart failure remains unclear. Here, we demonstrate that MERTK expression was upregulated in cardiac tissue macrophages of mice with pressure overload-induced heart failure. Deletion of MERTK ameliorated transverse aortic constriction (TAC)- and Ang II-induced cardiac hypertrophy and heart failure. This protective effect was associated with reduced type I interferon signaling and was reversed by interferon receptor activation. Efferocytosis assays were performed to demonstrate that mitochondrial double-stranded RNA from apoptotic cardiomyocytes activated Toll-like receptor 3 in macrophages, promoting Interferon beta (IFNb) expression. In vitro experiment identified that IFNb sensitized cardiomyocytes to Ang II stimulation by augmenting the P53 pathway, suppressing Ang II-induced protective mitophagy and promoting cardiomyocyte apoptosis. In conclusion, macrophage MERTK receptor exacerbated post-TAC heart failure and cardiac hypertrophy by mediating the phagocytosis of apoptotic cardiomyocytes and promoting IFNb expression. This study provides novel insights into the role of macrophage MERTK-mediated efferocytosis and type I interferon response in the pathogenesis of heart failure. These findings highlight an unrecognized function of MERTK in pressure overload-induced cardiac remodeling and identify IFNb as a key downstream effector of MERTK in this pathological process
2025-09-01 | GSE306545 | GEO
Project description:Cardiac macrophages (cMacs) elimination exacerbates pressure overload-induced heart failure. However, the role of functionally distinct subsets of cMacs in heart failure remains largely unknown. CD163, a macrophage-specific scavenger receptor expressed in a subset of cMacs, has been associated with cardiovascular events through its circulating soluble form. This study aimed to elucidate the functional role of the CD163+ cMacs subset in pressure overload-induced heart failure. Transverse aortic constriction (TAC) was used to induce pressure overload. TAC-induced left ventricular systolic dysfunction, characterized by reduced ejection fraction and fractional shortening, was significantly aggravated in Cd163−/− mice post-surgery. Genes differentially expressed due to CD163 deficiency were enriched in pathways related to mitochondrial bioenergetics and homeostasis. Transmission electron microscopy revealed an increase in dysfunctional mitochondria in cardiomyocytes of Cd163−/− mice post-TAC. Additionally, decreased serum interleukin (IL)-10 levels and reduced IL-10 expression in cMacs were observed in Cd163−/− mice post-TAC. IL-10 supplementation significantly reversed TAC-induced reductions in left ventricular systolic function in Cd163−/− mice and improved mitochondrial functions in cardiomyocytes. Furthermore, decreased IL-10 levels and increased soluble CD163 were identified as risk factors for heart failure in hypertensive patients. Thus, CD163 in cMacs attenuates pressure overload-induced left ventricular systolic dysfunction through IL-10.
2025-05-08 | GSE223346 | GEO
Project description:Background: In complex congenital heart disease patients such as those with tetralogy of Fallot, the right ventricle (RV) is subject to pressure overload, leading to RV hypertrophy and eventually RV failure. The mechanisms that promote the transition from stable RV hypertrophy to RV failure are unknown. We evaluated the role of mitochondrial bioenergetics in the development of RV failure. Methods: We created a murine model of RV pressure overload by pulmonary artery banding and compared with sham-operated controls. Gene expression by RNA-sequencing, oxidative stress, mitochondrial respiration, dynamics, and structure were assessed in pressure overload-induced RV failure. Results: RV failure was characterized by decreased expression of electron transport chain genes and mitochondrial antioxidant genes (aldehyde dehydrogenase 2 and superoxide dismutase 2) and increased expression of oxidant stress markers (heme oxygenase, 4-hydroxynonenal). The activities of all electron transport chain complexes decreased with RV hypertrophy and further with RV failure (oxidative phosphorylation: sham 552.3±43.07 vs. RV hypertrophy 334.3±30.65 vs. RV failure 165.4±36.72 pmol/(sec*ml), p<0.0001). Mitochondrial fission protein DRP1 did not change, while MFF decreased and fusion protein OPA1 decreased. In contrast, transcription of electron transport chain genes increased in the left ventricle of RV failure. Conclusion: Pressure overload-induced RV failure is characterized by decreased transcription and activity of electron transport chain complexes and increased oxidative stress which are associated with decreased energy generation. An improved understanding of the complex processes of energy generation could aid in developing novel therapies to mitigate mitochondrial dysfunction and delay the onset of RV failure.
2021-03-18 | GSE152413 | GEO
Project description:Expression profiles at various time points after surgical intervention for pressure-overload induced cardiac hypertrophy and failure.
2004-06-30 | E-MEXP-105 | biostudies-arrayexpress
Project description:To investigate the mechanism of chronic heart failure induced by pressure overload, we established an animal model in mice by transverse aortic constriction (TAC), with mice undergoing sham surgery as control.
2023-10-31 | GSE228199 | GEO
Project description:Pressure overload (PO) leads first to cardiac hypertrophy and later to heart failure. In mice, PO leads to sex differences in cardiac morphology and function. However, early sex differences in gene regulation that precede sex differences in function have not yet been identified. To identify such changes, we developed a model of PO that is characterized by compensated hypertrophy without sex differences after 2 weeks and by heart failure with sex differences after 9 weeks. We used transverse aortic constriction (TAC) or sham-operation in male and female mice and analyzed gene expression by microarray experiments. Experiment Overall Design: The gene expression induced by pressure overload in female and male mice in comparison to sham operated control mice was investigated. For each of these four conditions four biological replicates were performed and the individual samples were hybridized seperately on Affymetrix RAE 430A GeneChip Arrays.
2008-06-15 | E-GEOD-6970 | biostudies-arrayexpress
Project description:Proteo-transcriptional architecture of human pressure overload: implications for heart failure
| PRJNA1093010 | ENA
Project description:Chronic pressure overload initiates a series of molecular alterations in the human heart that predate macroscopic organ-level remodeling and downstream heart failure (HF). We hypothesized that integrating easily accessible circulating mediators (proteome) with their expression in the heart (transcriptome) may prioritize targets for study in human pressure overload. Among individuals with severe aortic stenosis (AS)—a pressure overload state—we measured the circulating proteome (Olink) and examined associations with myocardial structure/function (N=519), cardiac MRI-based tissue fibrosis (N=145), and outcomes in AS (N=802). We constructed proteomic signatures of cardiac remodeling and tested their association with HF in the UK Biobank (N=36,668). For proteo-transcriptional integration, we examined a "remodeling proteome” prioritized by proteome-phenotype relations at the transcriptional level via single nuclear RNA-sequencing (snRNA-seq) in 20 human hearts (11 with AS at the time of surgical aortic valve replacement [AVR] and 9 donor hearts not used for transplantation). We identified three principal components of myocardial remodeling (across 12 echocardiographic measures in 503 patients with AS) loaded on cardiac morphology, systolic, and diastolic function traits. Proteins associated with these components (the “remodeling proteome”) specified both known and novel mediators of fibrosis, hypertrophy, and oxidative stress, several of which were associated with interstitial fibrosis by cardiac MRI. Proteomic signatures of remodeling were strongly linked to mortality (AS cohort and UK Biobank) and incident HF (UK Biobank). At a myocardial level, we observed broad differential expression of genes encoding the remodeling proteome between AS and donor hearts, featuring convergent fibrosis pathways (WNT9A, ITGA6, AGRN, CRIM1, SEMA4C, LAYN, PTX3, HMOX1) and metabolic-inflammatory signaling (ENPP2/ATX, TNF), among others. Differential expression of proteo-transcriptionally prioritized genes was prominent in fibroblasts, cardiomyocytes, and endothelial cells. Proteo-transcriptional prioritization in human pressure overload hearts identifies both known and novel targets that are mechanistically relevant to HF pathogenesis. Future integrative studies to index circulating biomarkers over time to myocardial tissue level is warranted to inform pathways of HF progression.
2025-05-01 | GSE262690 | GEO
Project description:An important event in the pathogenesis of heart failure is the development of pathological cardiac hypertrophy. In cultured cardiac cardiomyocytes, the transcription factor Gata4 is required for agonist-induced cardiomyocyte hypertrophy. We hypothesized that in the intact organism Gata4 is an important regulator of postnatal heart function and of the hypertrophic response of the heart to pathological stress. To test this hypothesis, we studied mice heterozygous for deletion of the second exon of Gata4 (G4D). At baseline, G4D mice had mild systolic and diastolic dysfunction associated with reduced heart weight and decreased cardiomyocyte number. After transverse aortic constriction (TAC), G4D mice developed overt heart failure and eccentric cardiac hypertrophy, associated with significantly increased fibrosis and cardiomyocyte apoptosis. Inhibition of apoptosis by overexpression of the insulin-like growth factor 1 receptor prevented TAC-induced heart failure in G4D mice. Unlike WT-TAC controls, G4D-TAC cardiomyocytes hypertrophied by increasing in length more than width. Gene expression profiling revealed upregulation of genes associated with apoptosis and fibrosis, including members of the TGF? pathway. Our data demonstrate that Gata4 is essential for cardiac function in the postnatal heart. After pressure overload, Gata4 regulates the pattern of cardiomyocyte hypertrophy and protects the heart from load-induced failure. Keywords: genetic modification, pressure overload stress response
2006-08-12 | GSE5500 | GEO
Project description:Aims: In humans, secretome of pericardial (PAT) and epicardial adipose tissue (EAT) contribute to establishment of heart failure (HF) with preserved ejection fraction (HFpEF) originating from pressure-overload due to metabolic disorder. We examined whether PAT affects also manifestation and progression of pressure-induced HF in the absence of metabolic burden in mice. Methods and results: Progressive remodelling was assessed in C57BL/6J males, aged 9 wks, randomly assigned to sham surgery or transverse aortic constriction (TAC) for 1 week (early pressure-overload), 8 (chronic pressure-overload), or 12 weeks (HFrEF) with or without concomitant PAT excision. PAT removal did not affect early (1 wk TAC), and chronic (8 wks) pressure-overload induced concentric remodelling. However, the initial PAT excision prevented TAC-induced expansion of pro-inflammatory macrophages during early pressure-overload and attenuated the persistent LV expression of pro-hypertrophic, pro-inflammatory and pro-fibrotic factors as well as the drastic LV dilation and progressive systolic dysfunction in the long-term and thereby protected against the transition to HFrEF. This protection was associated with significant reduction of microscar and perivascular fibrosis. The latter was, at least in part, attributed to reduced accumulation of pro-fibrotic CD206+ macrophages around the coronaries 12 wks post-surgery in the absence of PAT compared to mice with intact PAT. In addition, PAT bulk RNA sequencing revealed the initiation of an extracellular matrix deposition programme in the PAT early upon TAC surgery, which might trigger fibrotic responses in the underlying myocardium. Indeed, isolated naive adult cardiac fibroblasts exposed to PAT lysate from 12 wks TAC mice increased collagen production and cell viability/proliferation. Conclusion: Our data suggest PAT to play divergent roles in the chronically pressure overloaded heart versus HFrEF - while widely not affecting concentric hypertrophy, PAT removal counteracts manifestation of HFrEF in mice, at least in part, by preventing excessive fibrotic and macrophage responses.
2024-12-06 | GSE283668 | GEO