YBX1 Drives Post-Myocardial Infarction Angiogenesis via an m⁶A-IGF2BP1/3 Dependent Stabilization of HIF-1α mRNA
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE313688 | GEO | 2026/01/18
REPOSITORIES: GEO
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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:<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:Tissue repair after myocardial infarction (MI) is guided by incompletely defined autocrine and paracrine-acting proteins. Deciphering these signals and their upstream triggers is essential when considering infarct healing as a therapeutic target. Searching for previously unknown growth factors involved in infarct repair, we performed a bioinformatic secretome analysis in cardiac endothelial cells and identified cysteine-rich with EGF-like domains 2 (CRELD2), an endoplasmic reticulum stress-inducible protein with poorly characterized function. CRELD2 was abundantly expressed and secreted in the heart after MI in mice and patients. Creld2-deficient mice and wild-type mice treated with a CRELD2-neutralizing antibody displayed impaired de novo microvessel formation in the infarct border zone and developed severe postinfarction heart failure. CRELD2 protein therapy, conversely, improved heart function after MI. Exposing human coronary artery endothelial cells to recombinant CRELD2 induced angiogenesis, associated with a distinct phosphoproteome signature. These findings identify CRELD2 as a novel angiogenic growth factor and unravel a link between endoplasmic reticulum stress and ischemic tissue repair.
2023-11-30 | PXD045013 | Pride
Project description:infarct size and subsequent deterioration in function. The identification of factors that enhance cardiac repair by the restoration of the vascular network is, therefore, of great significance. Here, we show that the transcription factor Zinc finger E-box-binding homeobox 2 (ZEB2) is increased in stressed cardiomyocytes and induces a cardioprotective cross-talk between cardiomyocytes and endothelial cells to enhance angiogenesis after ischemia. Single-cell sequencing indicates ZEB2 to be enriched in injured cardiomyocytes. Cardiomyocyte-specific deletion of ZEB2 results in impaired cardiac contractility and infarct healing post-myocardial infarction (post-MI), while cardiomyocyte-specific ZEB2 overexpression improves cardiomyocyte survival and cardiac function. We identified Thymosin 4 (TMSB4) and Prothymosin (PTMA) as main paracrine factors released from cardiomyocytes to stimulate angiogenesis by enhancing endothelial cell migration, and whose regulation is validated in our in vivo models. Therapeutic delivery of ZEB2 to cardiomyocytes in the infarcted heart induces the expression of TMSB4 and PTMA, which enhances angiogenesis and prevents cardiac dysfunction. These findings reveal ZEB2 as a beneficial factor during ischemic injury, which may hold promise for the identification of new therapies.
2021-03-23 | PXD022212 | Pride
Project description:Post-myocardial infarction (Post-MI) heart failure is an unanswered clinical challenge. Current immunological intervention trials to reduce MI damage are unsatisfactory. Tbx1, the major 22q11.2 deletion syndrome (22q11.2DS) disease gene, reactivated in cardiac lymphatic endothelial cells (LECs) to promote post-MI repair. Endothelial deletion of Tbx1 deteriorated post-MI cardiac function. To identify the initial endothelial-derived gene expression changes that are responsible for lymphangiogenesis and cell non-autonomous functions towards immune cells after MI, we enriched CD31+ endothelial cells from 5 dpMI Ctrl and Tbx1cko hearts and performed RNA-seq. In conclusion, our findings revealed that Tbx1 can promote lymphangiogenesis and alleviate excessive cardiac inflammation in post MI hearts.
2023-08-28 | GSE137063 | GEO
Project description:Objectives: To investigate the role of ALKBH5 in fibroblasts during post-myocardial infarction (MI) repair. Background: N6-methyladenosine (m6A) mRNA modification has been shown to play an important role in cardiovascular diseases. The RNA demethylase, AlkB homolog 5 (ALKBH5), is an m6A "eraser" that is responsible for decreased m6A methylation. However, its role in cardiac fibroblasts during the post-MI healing process remains elusive. Methods: MI was mimicked by permanent left anterior descending artery ligation in global ALKBH5-knockout, ALKBH5-knockin, and fibroblast-specific ALKBH5-knockout mice to study the function of ALKBH5 during post-MI collagen repair. Methylated RNA immunoprecipitation sequencing was performed to explore potential ALKBH5 targets. Results: Dramatic alterations in ALKBH5 expression were observed during the early stage post-MI and in hypoxic fibroblasts. Global ALKBH5 knockin reduced infarct size and improved cardiac function after MI. The global and fibroblast-specific ALKBH5-knockout mice both exhibited low survival rates along with poor collagen repair, impaired cardiac function, and cardiac rupture. Both in vivo and in vitro ALKBH5 loss led to impaired fibroblast activation and decreased collagen deposition. Additionally, hypoxia, but not TGF-β1 or Ang II, upregulated ALKBH5 expression in myofibroblasts in a HIF-1α-dependent transcriptional manner. Mechanistically, ALKBH5 promoted the stability of ErbB4 mRNA and the degradation of ST14 mRNA via m6A demethylation. Fibroblast-specific ErbB4 overexpression ameliorated the impaired fibroblast-to-myofibroblast transformation and poor post-MI repair due to ALKBH5 knockout. Conclusions: Fibroblast ALKBH5 positively regulates post-MI healing via post-transcriptional modification and stabilization of ErbB4 mRNA in an m6A-dependent manner. Targeting ALKBH5/ERBB4 may be a potential therapeutic option for post-MI cardiac rupture.
2023-10-01 | GSE226415 | GEO
Project description:Gene expression alterations in myocardial tissues following acute myocardial infarction (AMI) are of great significance for studying the pathophysiological mechanisms of this disease. RNA-seq was used to analyse the gene expression levels in myocardial tissues both in a mouse left anterior descending coronary artery (LAD) ligation model at the 4th day after MI and in sham-operated mice.We uncovered the upregulation of several angiogenesis-related genes after MI, which provided a basis for researches on cardiac repair following AMI.
2025-09-27 | GSE308783 | GEO
Project description: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. 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. 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.
2025-09-17 | PXD068507 |
Project description:Ischemia, fibrosis, and remodeling lead to heart failure after severe myocardial infarction (MI). Myoblast sheet transplantation is a promising therapy to enhance cardiac function and induce therapeutic angiogenesis via a paracrine mechanism in this detrimental disease. We hypothesized that in a rat model of MI-induced chronic heart failure this therapy could further be improved by overexpression of the antiapoptotic, antifibrotic, and proangiogenic hepatocyte growth factor (HGF) in the myoblast sheets. We studied the ability of wild type (L6-WT) and human HGF-expressing (L6-HGF) L6 myoblast sheet-derived paracrine factors to stimulate cardiomyocyte, endothelial cell, or smooth muscle cell migration in culture. Further, we studied the autocrine effect of hHGF-expression on myoblast gene expression using microarray analysis. We induced MI in Wistar rats by left anterior descending coronary artery (LAD) ligation and allowed heart failure to develop for four weeks. Thereafter, we administered L6-WT (n=15) or L6-HGF (n=16) myoblast sheet therapy. Control rats (n=13) underwent LAD ligation and rethoracotomy without therapy and five rats underwent sham-operation in both surgeries. We evaluated cardiac function with echocardiography at 2 and 4 weeks after therapy administration. We analyzed cardiac angiogenesis and left ventricular architecture from histological sections 4 weeks after therapy. Paracrine mediators from L6-HGF myoblast sheets effectively induced migration of cardiac endothelial and smooth muscle cells but not cardiomyocytes. Microarray data revealed that hHGF-expression modulated myoblast gene expression. In vivo, L6-HGF sheet therapy effectively stimulated angiogenesis in the infarcted and non-infarcted areas. Both L6-WT and L6-HGF therapies enhanced cardiac function and inhibited remodeling in a similar fashion. In conclusion, L6-HGF therapy effectively induced angiogenesis in the chronically failing heart. Cardiac function, however, was not further enhanced by hHGF-expression. Analysis of the L6 rat skeletal myoblast cell line and myoblast cell sheets with constitutive human HGF expression.
2010-12-10 | E-GEOD-25752 | biostudies-arrayexpress
Project description:BACKGROUND: Myocardial infarction (MI), a leading cause of death globally, continues to pose significant clinical challenges due to the constraints of existing treatment options. The cardiac vascular system, which forms the essential framework supporting myocardial function, delivers oxygen and nutrients with precise regulation to heart tissue. Nevertheless, the complex regulatory processes controlling this network after MI remain not fully understood. Importantly, the central involvement of cardiac endothelial cells in the pathophysiological development of MI necessitates more in-depth investigation. METHODS: We investigated changes in the expression of Signal Peptide, CUB Domain And EGF Like Domain Containing 3 (SCUBE3) protein in the myocardium from MI-affected mice and human MI cardiac tissues. Using genetically modified mouse models alongside various cellular and molecular biology methods, we thoroughly explored the functional role of SCUBE3 in MI and its mechanisms related to cardiac endothelial cell metabolism. RESULTS: Proteomic analysis of serum from MI patients revealed a significant increase in SCUBE3 protein levels. Immunohistochemical studies showed a pronounced elevation of SCUBE3 predominantly localized in fibroblasts within the infarcted regions of cardiac tissues from MI patients. Similarly, in a mouse MI model, SCUBE3 expression was upregulated and mainly found in fibroblasts in the damaged myocardial areas. Through inducible, fibroblast-specific SCUBE3 overexpression and knockout mouse models, we found that SCUBE3 overexpression significantly promoted angiogenesis after MI, enhanced microvascular network integrity, and mitigated myocardial damage. Conversely, deletion of SCUBE3 worsened cardiac injury following infarction. Subsequent protein interaction assays and mass spectrometry identified that SCUBE3 specifically binds to and activates vascular endothelial growth factor receptor 1 (VEGFR1) on endothelial cells, triggering downstream signaling pathways. Transcriptomic analysis demonstrated that SCUBE3 substantially upregulates pathways related to fatty acid metabolism. Live-cell dynamic studies confirmed that SCUBE3 facilitates fatty acid uptake and increases metabolic activity in endothelial cells. Metabolomic profiling further indicated that SCUBE3 aids in converting unsaturated fatty acids into phosphosugars and nucleotides, providing critical substrates and energy to support endothelial proliferation. In SCUBE3-overexpressing mice, endothelial cell–specific inducible deletion of VEGFR1 completely abolished SCUBE3-induced fatty acid metabolism and its cardioprotective benefits. Additionally, beyond its angiogenic function, SCUBE3 notably improves cardiomyocyte regenerative ability, underscoring its potential as a novel therapeutic target for myocardial repair.
2025-09-18 | PXD068476 |