Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1001173 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25580072_1.fastq.gz | Fastqsanger.gz | |||
| SRR25580072_2.fastq.gz | Fastqsanger.gz | |||
| SRR25580073_1.fastq.gz | Fastqsanger.gz | |||
| SRR25580073_2.fastq.gz | Fastqsanger.gz | |||
| SRR25580074_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 24 |
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Project description:La ribonucleoprotein 6, Translational Regulator (LARP6), a multifunctional mRNA binding protein with well-described pro-fibrotic effects, increases type I collagen mRNA half-life, translation, and deposition in non-cardiac tissues. In the heart LARP6 is expressed in cardiomyocytes, not primarily involved in fibrosis, where its role is unknown. To investigate the role of cardiomyocyte-derived LARP6 on cardiac function and remodeling, we generated a cardiomyocyte-specific LARP6 overexpressing transgenic mouse model (LARP6-Tg). Baseline longitudinal studies up to 10 months of age revealed that constitutive overexpression of LARP6 had no significant effect on cardiac function or morphology despite inducing mild interstitial fibrosis versus wild-type littermates (WT). Subsequently, we hypothesized that cardiomyocyte-specific LARP6-Tg mice would exhibit exacerbated cardiac remodeling and dysfunction in response to hypertensive stress via angiotensin II (Ang II) infusion. Ang II (1000 ng/kg/min for 21 days) induced hypertension and cardiac hypertrophy in WT and LARP6-Tg mice of both sexes. Unexpectedly, Ang II-induced cardiac dysfunction was prevented in LARP6-Tg mice. Cardiac gene expression profiling predicted increased fibrosis and cardiomyocyte death in Ang II-treated WT mice and inhibition of cardiomyocyte death in Ang II-treated LARP6-Tg mice, versus saline-treated controls. Surprisingly, Ang II-induced interstitial fibrosis was reduced in LARP6-Tg mice and associated with attenuation of cardiomyocyte cell death and reduced myofibroblast activation. These data support a mild pro-fibrotic action of cardiomyocyte LARP6 in unstressed mice and, paradoxically, that LARP6 overexpression is sufficient to prevent Ang II-induced cardiac interstitial fibrosis and dysfunction. Sustained induction of LARP6 has therapeutic potential in hypertensive heart disease.
2025-01-31 | GSE284286 | GEO
Project description:Increased level of angiotensin II (Ang II) plays a central role in the development of hypertensive vascular remodeling. Here, we identify the deubiquitinating enzyme JOSD2 as a protective factor and investigate its molecular mechanism in Ang II-induced vascular remodeling. Firstly, we found that JOSD2 was up-regulated in aortic smooth muscle cells but not endothelial cells of Ang II-challenged mouse vascular tissues. Whole-body knockout of JOSD2 significantly deteriorated Ang II-induced vascular remodeling in mice. Conversely, Ang II-induced vascular remodeling was reversed by VSMC-specific JOSD2 overexpression. In vitro, JOSD2 deficiency aggravated the fibrosis, proliferation, and migration induced by Ang II in vascular smooth muscle cells (VSMCs), while these changes were reversed by JOSD2 overexpression. RNA-seq analysis showed that the protective effects of JOSD2 in VSMCs were related to TGFβ-SMAD pathway. Furthermore, the LC-MS/MS analysis identified SMAD7, a negative regulator in TGFβ-SMAD pathway, as the substrate of JOSD2. JOSD2 specifically bound to the MH1 domain of SMAD7 to removed K48-linked Ub chains of SMAD7 at lysine 220 to sustain SMAD7 stability. Taken together, our finding reveals that JOSD2-SMAD7 axis is critical for relieving Ang II-induced vascular remodeling and JOSD2 maybe a novel and potential therapeutic target for hypertensive vascular remodeling.
2024-10-10 | PXD056674 | Pride
Project description:Increased level of angiotensin II (Ang II) plays a central role in the development of hypertensive vascular remodeling. Here, we identify the deubiquitinating enzyme JOSD2 as a protective factor and investigate its molecular mechanism in Ang II-induced vascular remodeling. Firstly, we found that JOSD2 was up-regulated in aortic smooth muscle cells but not endothelial cells of Ang II-challenged mouse vascular tissues. Whole-body knockout of JOSD2 significantly deteriorated Ang II-induced vascular remodeling in mice. Conversely, Ang II-induced vascular remodeling was reversed by VSMC-specific JOSD2 overexpression. In vitro, JOSD2 deficiency aggravated the fibrosis, proliferation, and migration induced by Ang II in vascular smooth muscle cells (VSMCs), while these changes were reversed by JOSD2 overexpression. RNA-seq analysis showed that the protective effects of JOSD2 in VSMCs were related to TGFβ-SMAD pathway. Furthermore, the LC-MS/MS analysis identified SMAD7, a negative regulator in TGFβ-SMAD pathway, as the substrate of JOSD2. JOSD2 specifically bound to the MH1 domain of SMAD7 to removed K48-linked Ub chains of SMAD7 at lysine 220 to sustain SMAD7 stability. Taken together, our finding reveals that JOSD2-SMAD7 axis is critical for relieving Ang II-induced vascular remodeling and JOSD2 maybe a novel and potential therapeutic target for hypertensive vascular remodeling.
2024-10-18 | GSE279358 | GEO
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:Pathological cardiac hypertrophy is a key predisposing factor for heart failure (HF). This study investigates the role of the E3 ubiquitin ligase Tripartite Motif-Containing 40 (TRIM40) in cardiac hypertrophy. Using TRIM40 knockout (TRIM40-/-) and cardiac-specific overexpressing mice, pathological hypertrophy was induced by angiotensin II (Ang II) infusion or transverse aortic constriction (TAC). Results demonstrated that TRIM40 expression was upregulated in hypertrophic hearts. TRIM40 deficiency attenuated cardiac hypertrophy and dysfunction, whereas its overexpression exacerbated pathological remodeling. Mechanistically, TRIM40 binds Protein Kinase N2 (PKN2) via its B-box domain, promoting K63-linked ubiquitination at cysteine 29 that enhances PKN2 phosphorylation at Ser815 and activates downstream signaling. Pharmacological inhibition of PKN2 attenuated cardiac remodeling induced by TRIM40 overexpression. These findings indicate that TRIM40 promotes cardiac hypertrophy through K63-linked ubiquitination and activation of PKN2, identifying TRIM40 as a potential therapeutic target for HF.
2025-12-21 | GSE314005 | GEO
Project description:Analysis of sodium butyrate（NaBu） on angiotensin II（Ang II-induced cardiac fibrosis at gene expression level. The hypothesis tested in the present study was that NaBu influence the balance of gene expression of Ang II-induce cardiac fibrosis. Results provide important information of the response of NaBu to cardiac fibrosis, such as specific genes, up- or down-regulated specific cardiac cellular functions.
2021-12-01 | GSE142436 | GEO
Project description:Cardiac fibrosis is a common pathological feature of various cardiac diseases that contributes significantly to heart failure progression and poor clinical outcomes. Recent genetic studies have shown that lower expression of CUB domain-containing protein 1 (CDCP1) is linked to myocardial recovery, but its direct role in cardiac pathophysiology remains unkown. In this study, we investigated the functional contribution of CDCP1 to pressure overload-induced cardiac remodeling and fibrosis. CDCP1 deletion attenuated Ang II/PE-induced cardiac dysfunction as demonstrated by reduced left ventricular mass index and improved cardiac function compared to wild-type controls. Histological analysis revealed significantly decreased cardiac fibrosis in CDCP1-KO mice. Transcriptomic profiling revealed that CDCP1 KO attenuates cardiac fibrosis through downregulation of matrix metalloproteases, collagen biosynthesis and limiting the pathological remodeling extracellular matrix. Spatial transcriptomics further revealed region-specific alterations in fibrotic and inflammatory signatures among the subtypes of cardiomyocytes and fibroblasts, suggesting localized CDCP1-dependent effects on cardiac remodeling. Our findings establish CDCP1 as a critical regulator of pressure overload-induced cardiac fibrosis and dysfunction. Our work provides direct evidence supporting CDCP1 inhibition as a potential therapeutic strategy for cardiac fibrosis.
2025-12-01 | GSE303631 | GEO
Project description:Heart failure is a fairly common outcome of hypertension. Recent studies have highlighted the key role of the non-hemodynamic activity of angiotensin II (Ang II) in hypertensive heart failure via inducing cardiac inflammation. Drugs that disrupt Ang II-induced cardiac inflammation may have clinical utility in the treatment of hypertensive heart failure. A naturally occurring compound, corynoline, exhibit anti-inflammatory activities in other systems. C57BL/6 mice were injected with Ang II via a micro-osmotic pump for four weeks to develop hypertensive heart failure. The mice were treated with corynoline by gavage for two weeks. RNA-sequencing analysis was performed to explore the potential mechanism of corynoline. We found that corynoline could inhibit inflammation, myocardial fibrosis, and hypertrophy to prevent heart dysfunction, without the alteration of blood pressure. RNA-sequencing analysis indicates that the PPARα pathway is involved Ang II-induced cardiac fibrosis and cardiac remodeling. Corynoline reversed Ang II-induced PPARα inhibition both in vitro and in vivo. We further found that corynoline increases the interaction between PPARα and P65 to inhibit the NF-κB pro-inflammatory pathway in H9c2 cells. Our studies show that corynoline relieves Ang II-induced hypertensive heart failure by increasing the interaction between PPARα and P65 to inhibit the NF-κB pathway.
2022-04-09 | GSE200279 | GEO
Project description:Metabolic reprogramming is critical in the onset of pressure overload-induced cardiac remodeling. Our study reveals that proline dehydrogenase (PRODH), the key enzyme in proline metabolism, reprograms cardiomyocyte metabolism to protect against cardiac remodeling. We induced cardiac remodeling using transverse aortic constriction (TAC) in both cardiac-specific PRODH knockout and overexpression mice. Our results indicate that PRODH expression is suppressed post-TAC. Cardiac-specific PRODH knockout mice exhibited worsened cardiac dysfunction, while mice with PRODH overexpression demonstrated a protective effect. Additionally, we simulated cardiomyocyte hypertrophy in vitro using neonatal rat ventricular myocytes treated with phenylephrine. Through RNA sequencing, metabolomics, and metabolic flux analysis, we elucidated that PRODH overexpression in cardiomyocytes redirects proline catabolism to replenish tricarboxylic acid (TCA) cycle intermediates, enhance energy production, and restore glutathione redox balance. In summary, our findings suggest PRODH as a modulator of cardiac bioenergetics and redox homeostasis duing cardiac remodeling induced by pressure overload. This highlights the potential of PRODH as a therapeutic target for cardiac remodeling.
2025-02-28 | GSE260465 | GEO
Project description:Metabolic reprogramming is critical in the onset of pressure overload-induced cardiac remodeling. Our study reveals that proline dehydrogenase (PRODH), the key enzyme in proline metabolism, reprograms cardiomyocyte metabolism to protect against cardiac remodeling. We induced cardiac remodeling using transverse aortic constriction (TAC) in both cardiac-specific PRODH knockout and overexpression mice. Our results indicate that PRODH expression is suppressed post-TAC. Cardiac-specific PRODH knockout mice exhibited worsened cardiac dysfunction, while mice with PRODH overexpression demonstrated a protective effect. Additionally, we simulated cardiomyocyte hypertrophy in vitro using neonatal rat ventricular myocytes treated with phenylephrine. Through RNA sequencing, metabolomics, and metabolic flux analysis, we elucidated that PRODH overexpression in cardiomyocytes redirects proline catabolism to replenish tricarboxylic acid (TCA) cycle intermediates, enhance energy production, and restore glutathione redox balance. In summary, our findings suggest PRODH as a modulator of cardiac bioenergetics and redox homeostasis duing cardiac remodeling induced by pressure overload. This highlights the potential of PRODH as a therapeutic target for cardiac remodeling.
2025-02-28 | GSE260464 | GEO