Cardiomyocyte-Derived HSPB1 Regulates TGF-β1 Maturation and Inhibits Endothelial-to-Mesenchymal Transition in Myocardial Fibrosis after Infarction
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Xiehong Liu
PROVIDER: PXD072325 | iProX | Mon Dec 22 00:00:00 GMT 2025
REPOSITORIES: iProX
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Project description:In the healing process of myocardial infarction, cardiac fibroblasts are activated to produce collagen, leading to adverse remodeling and heart failure. Our previous study showed that ASPP1 promotes cardiomyocyte apoptosis by enhancing nuclear trafficking of p53. We thus explored the influence of ASPP1 on myocardial fibrosis and the underlying mechanisms. Here, we observed ASPP1 was increased after 4 weeks of MI. Both global and myofibroblast knockout of ASPP1 in mice mitigated cardiac dysfunction and fibrosis after MI. Strikingly, ASPP1 produced opposite influence on p53 level and cell fate in cardiac fibroblasts and cardiomyocytes. Knockdown of ASPP1 increased p53 level and inhibited the activity of cardiac fibroblasts. ASPP1 accumulated in the cytoplasm of fibroblasts while the level of p53 was reduced following TGF-1 stimulation; however, inhibition of ASPP1 increased p53 level and promoted p53 nuclear translocation. Mechanistically, ASPP1 directly bound to deubiquitinase OTUB1, thereby promoting the ubiquitination and degradation of p53, attenuating myofibroblast activity and cardiac fibrosis, and improving heart function after MI.
2025-01-18 | PXD055651 | Pride
Project description:To further search for potential gene targets which are involved in the pathological process of myocardial infarction, we have employed whole genome microarray expression profiling as a discovery platform to identify the expression of STAT6, β1-adrenergic receptors and inflammatory cytokines. The CD11b+ cells were isolated from spleen and bone marrow of mice by magnetic beads, and the experimental mice were divided into four time points (control, MI 1week, MI 2 weeks, and MI 4 weeks). We found the β1-AR related sympathetic signal, the STAT6 signal and inflammatory cytokines (IL-1α, IL-18 and TGF-β) are involved in the activation of CD11b+ immune cells and cardiac fibrogenesis after myocardial infarction.
2020-11-16 | GSE154733 | GEO
Project description:In this study, we used a cardiac-specific, inducible expression system to activate YAP in adult mouse heart. Activation of YAP in adult heart promoted cardiomyocyte proliferation and did not deleteriously affect heart function. Furthermore, YAP activation after myocardial infarction (MI) preserved heart function and reduced infarct size. Using adeno-associated virus subtype 9 (AAV9) as a delivery vector, we expressed human YAP in the murine myocardium immediately after MI. We found that AAV9:hYAP significantly improved cardiac function and mouse survival. AAV9:hYAP did not exert its salutary effects by reducing cardiomyocyte apoptosis. Rather, we found that AAV9:hYAP stimulated adult cardiomyocyte proliferation. Gene expression profiling indicated that AAV9:hYAP stimulated cell cycle gene expression, enhanced TGFβ-signaling, and activated of components of the inflammatory response.Cardiac specific YAP activation after MI mitigated myocardial injury after MI, improved cardiac function and mouse survival. These findings suggest that therapeutic activation of hYAP or its downstream targets, potentially through AAV-mediated gene therapy, may be a strategy to improve outcome after MI. Three groups were involved in this study: sham group, AAV9:Luci+MI group and AAV9-YAP+MI group. Each group contained three biological replicates. The sham group had neither myocardial infarction nor AAV injection. The AAV9:Luci +MI(L for brief) group had myocardial infarction and injected with AAV9:Luic. The AAV9:hYAP+MI(YAP for brief) group had myocardial infarction and injected with AAV9:hYAP. 5 days after MI and AAV injection, the heart apexes were collected and the total RNA were isolated for microarray analysis.
2014-05-26 | E-GEOD-54612 | biostudies-arrayexpress
Project description:Myocardial infarctions cause hypoxic injury to downstream tissue and a consequent fibrotic remodeling process to replace injured tissue with a scar. Scar formation occurs through phases of wound healing in which stimuli such as transforming growth factor-beta (TGF-β) drive cardiac fibroblasts to activate into a myofibroblast phenotype and deposit matrix molecules that form a scar. While this is necessary to repair injured tissue, excessive fibrosis commonly occurs which is correlated with heart failure. Therefore, defining cardiac fibroblast phenotypes under hypoxic stimuli and TGF-β is essential for understanding and treating pathological fibrosis. We robustly characterized fibroblast phenotype through immunofluorescence, quantitative RT-PCR, and proteomic analysis, after either TGF-β treatment or hypoxia durations that mimic acute hypoxic injury post-infarction. We find that hypoxic fibroblasts respond to low oxygen with increased hypoxia inducible factor 1 (HIF-1) but not HIF-2 activity by 4h. This is accompanied by increased gene and protein levels of VEGFA and LOX, respectively, which are both targets of HIF-1. Both TGF-β1 and hypoxia inhibit proliferation by 24h. While TGF-β1 treatment upregulated various fibrotic pathways, hypoxia causes a global reduction in protein synthesis, including collagen biosynthesis. This study discerns overlapping from distinctive outcomes of TGF-β1 and hypoxia treatment, which is important for elucidating their roles in fibrotic remodeling post-MI.
2024-07-03 | PXD051197 | Pride
Project description:The heart suffers from a severe loss of cardiomyocyte after myocardial infarction (MI). However, it is not known which type of cell death is the major contributor of the loss of cardiomyocytes. By studying a mouse heart MI model at a regenerative and a non-regenerative stage, we demonstrate that ferroptosis, not apoptosis or necroptosis, is the major contributor to cardiomyocyte death starting at 1 day-post-MI. Intrinsic Pitx2 signaling in cardiomyocyte prevents ferroptosis. Meanwhile, cardiac fibroblasts expressing high level of Fth1 interact with cardiomyocytes to share the iron burden, therefore inhibit cardiomyocyte ferroptosis. Cardiomyocyte Pitx2 also inhibits Tsp1 expression, therefore negatively regulate fibroblast-to-myofibroblast activation to limit fibrosis.
2023-06-02 | GSE211568 | GEO
Project description:<p>BACKGROUND: Myocardial infarction (MI), one of the leading causes of mortality worldwide, remains a clinical challenge due to limitations in current therapeutic strategies. The cardiac vascular network, as the fundamental architecture sustaining myocardial function, delivers oxygen and nutrients with high precision to the heart tissue. However, the dynamic regulatory mechanisms governing this network post-MI remain incompletely elucidated. Notably, the pivotal role of cardiac endothelial cells in the pathophysiological progression of MI calls for further comprehensive investigation.</p><p>METHODS: We examined alterations in Signal Peptide, CUB Domain And EGF Like Domain Containing 3 (SCUBE3) protein expression in the myocardium of MI-afflicted mice and human MI heart tissues. Utilizing genetically engineered mouse models in combination with diverse cellular and molecular biology techniques, we systematically dissected the functional role of SCUBE3 in MI and its underlying mechanisms in cardiac endothelial cell metabolism.</p><p>RESULTS: Proteomic profiling of serum samples from MI patients demonstrated a significant elevation in SCUBE3 protein levels. Immunohistochemical assessment revealed markedly increased SCUBE3 expression localized predominantly within fibroblasts in the infarct zone of cardiac tissues from MI patients. Consistently, in a murine MI model, SCUBE3 expression was also upregulated and primarily distributed in fibroblasts within the infarcted myocardial regions. Employing inducible, fibroblast-specific SCUBE3 overexpression and knockout mouse models, we observed that SCUBE3 overexpression robustly enhanced post-MI angiogenesis, improved microcirculatory network integrity, and attenuated myocardial injury. In contrast, SCUBE3 ablation exacerbated infarct-induced cardiac damage. Subsequent protein tracking and mass spectrometry analyses demonstrated that SCUBE3 selectively binds to and activates vascular endothelial growth factor receptor 1 (VEGFR1) on endothelial cells, thereby mediating downstream biological effects. Transcriptomic sequencing revealed that SCUBE3 significantly upregulates fatty acid metabolism–related pathways. Live-cell dynamic analysis further confirmed that SCUBE3 promotes fatty acid uptake and enhances the metabolic activity of endothelial cells. Metabolomic profiling indicated that SCUBE3 facilitates the conversion of unsaturated fatty acids into phosphosugars and nucleotides, supplying essential substrates and energy to support endothelial cell proliferation. In SCUBE3-overexpressing mice, endothelial cell–specific inducible VEGFR1 knockout completely abrogated SCUBE3-driven fatty acid metabolism and its associated cardioprotective effects. Moreover, beyond its role in angiogenesis SCUBE3 also markedly enhances cardiomyocyte regenerative capacity, highlighting its potential as a novel therapeutic target for myocardial repair.</p>
2025-09-18 | MTBLS13005 | MetaboLights
Project description:<p>BACKGROUND: Myocardial infarction (MI), one of the leading causes of mortality worldwide, remains a clinical challenge due to limitations in current therapeutic strategies. The cardiac vascular network, as the fundamental architecture sustaining myocardial function, delivers oxygen and nutrients with high precision to the heart tissue. However, the dynamic regulatory mechanisms governing this network post-MI remain incompletely elucidated. Notably, the pivotal role of cardiac endothelial cells in the pathophysiological progression of MI calls for further comprehensive investigation.</p><p>METHODS: We examined alterations in Signal Peptide, CUB Domain And EGF Like Domain Containing 3 (SCUBE3) protein expression in the myocardium of MI-afflicted mice and human MI heart tissues. Utilizing genetically engineered mouse models in combination with diverse cellular and molecular biology techniques, we systematically dissected the functional role of SCUBE3 in MI and its underlying mechanisms in cardiac endothelial cell metabolism.</p><p>RESULTS: Proteomic profiling of serum samples from MI patients demonstrated a significant elevation in SCUBE3 protein levels. Immunohistochemical assessment revealed markedly increased SCUBE3 expression localized predominantly within fibroblasts in the infarct zone of cardiac tissues from MI patients. Consistently, in a murine MI model, SCUBE3 expression was also upregulated and primarily distributed in fibroblasts within the infarcted myocardial regions. Employing inducible, fibroblast-specific SCUBE3 overexpression and knockout mouse models, we observed that SCUBE3 overexpression robustly enhanced post-MI angiogenesis, improved microcirculatory network integrity, and attenuated myocardial injury. In contrast, SCUBE3 ablation exacerbated infarct-induced cardiac damage. Subsequent protein tracking and mass spectrometry analyses demonstrated that SCUBE3 selectively binds to and activates vascular endothelial growth factor receptor 1 (VEGFR1) on endothelial cells, thereby mediating downstream biological effects. Transcriptomic sequencing revealed that SCUBE3 significantly upregulates fatty acid metabolism–related pathways. Live-cell dynamic analysis further confirmed that SCUBE3 promotes fatty acid uptake and enhances the metabolic activity of endothelial cells. Metabolomic profiling indicated that SCUBE3 facilitates the conversion of unsaturated fatty acids into phosphosugars and nucleotides, supplying essential substrates and energy to support endothelial cell proliferation. In SCUBE3-overexpressing mice, endothelial cell–specific inducible VEGFR1 knockout completely abrogated SCUBE3-driven fatty acid metabolism and its associated cardioprotective effects. Moreover, beyond its role in angiogenesis SCUBE3 also markedly enhances cardiomyocyte regenerative capacity, highlighting its potential as a novel therapeutic target for myocardial repair. Conclusions: Our findings establish that fibroblast-derived SCUBE3 interacts with VEGFR1 on endothelial cells to promote fatty acid metabolism, thereby providing energy substrates necessary for endothelial proliferation. This study elucidates the critical function of the SCUBE3–VEGFR1 signaling axis in post-MI vascular regeneration through metabolic regulation, presenting a promising avenue for therapeutic intervention in cardiac repair.</p>
2025-09-18 | MTBLS13004 | MetaboLights
Project description:Background and aims: Atrial fibrosis represents a critical determinant in atrial fibrillation (AF) pathogenesis. Although endothelial dysfunction is a hallmark feature of AF, the precise mechanisms by which endothelial cells (ECs) contribute to atrial fibrosis remain incompletely understood. Methods: This study employed single-cell RNA sequencing (scRNA-seq) to analyze intercellular communication networks in atrial tissues from both sinus rhythm (SR) and AF patients. Cdh5-CreERT2;RFP mice were generated to track endothelial plasticity following transverse aortic constriction (TAC). Cell-cell interactions were investigated using isolated human primary atrial ECs and fibroblasts (FBs) in vitro. To elucidate the regulatory role of endothelial-derived TGF-β1 on FB function, endothelial-specific Tgf-β1 knockout (Tgf-β1ECKO) mice were generated. Results: scRNA-seq analysis identified ECs as predominant signal-sending cells with extensive FB connectivity in both SR and AF atrial tissues. During fibrosis progression, ECs displayed significant mesenchymal activation at the transcriptional level. However, immunofluorescence and high-content screening revealed minimal complete endothelial-to-FB transition. Cell-cell communication analysis and in vitro studies identified TGF-β1 as the key mediator through which mesenchymal-activated ECs (EndoMA) promoted FB proliferation and collagen production. Notably, endothelial-specific Tgf-β1 deletion attenuated TAC-induced atrial fibrosis and reduced AF susceptibility. Conclusions: Our findings demonstrate that EndoMA-derived TGF-β1 critically regulates FB function and drives atrial fibrosis progression. Targeting endothelial-specific pathways represents a promising therapeutic strategy for attenuating atrial fibrosis in AF pathogenesis.
2025-08-27 | GSE198204 | GEO
Project description:Promoting the proliferation of endogenous cardiomyocytes represents a promising strategy for treating cardiac injuries. Identifying key factors that regulate cardiomyocyte proliferation can advance the development of novel therapies for heart regeneration. Here we identify that FOXK1 and FOXK2 act as master regulators of cardiomyocyte proliferation and metabolism. The expression of FOXK1 and FOXK2 decreased with postnatal heart development. Cardiomyocyte-specific knockout of Foxk1 or Foxk2 inhibited neonatal heart regeneration after myocardial infarction (MI) injury. Conversely, AAV9-mediated cardiomyocyte-specific overexpression of FOXK1 or FOXK2 prolonged the postnatal proliferative window of cardiomyocytes and enhanced cardiac repair in adult mice by promoting endogenous cardiomyocyte proliferation after MI. Mechanistically, FOXK1 and FOXK2 induce Ccnb1 and Cdk1 transcription and cardiomyocyte cell cycle progression, respectively. Ccnb1 knockdown hindered FOXK1 overexpression-induced cardiomyocyte proliferation, and the same effect was observed when Cdk1 was knocked down in FOXK2 overexpressing cardiomyocytes. Additionally, we further revealed that FOXK1 and FOXK2 induced a metabolic shift toward glycolysis by promoting HIF1α expression in cardiomyocytes, which favors cardiomyocyte proliferation. Our findings identify FOXK1 and FOXK2 as critical triggers of cardiomyocyte proliferation and define these two transcription factors as novel therapeutic targets for myocardial infarction.
2025-02-13 | MTBLS12191 | MetaboLights
Project description:Biological Relevance and Intent of the Experiment: The objective of this study is to elucidate the role of Cdk1 in cardiac function, specifically its contribution to cardiomyocyte proliferation and response to injury. Using a heart-specific Cdk1 knockout mouse model, we investigate the molecular and cellular impact of Cdk1 deficiency in the context of myocardial infarction (MI). Cdk1 is known for its regulatory functions in cell cycle progression, and its absence may significantly affect cardiac repair mechanisms post-MI. This research aims to explore whether the lack of Cdk1 impairs cardiomyocyte regeneration or promotes maladaptive remodeling, leading to compromised cardiac function.
2024-12-02 | E-MTAB-14508 | biostudies-arrayexpress