The Role of the Notch Signaling Pathway in Recovery of Cardiac Function after Myocardial Infarction

Kachanova, Olga; Lobov, Arseniy A.; Malashicheva, Anna

doi:10.3390/ijms232012509

Cited by 27 publications

(17 citation statements)

References 67 publications

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“…In this study, we applied WGCNA to the GSE141910 dataset to identify two modules that strongly correlated with CD8 + T-cells for subsequent analysis. The genes within the brown module were predominantly enriched in the Notch signaling pathway which exerts cardioprotective effects on the progression of HF by preventing apoptosis, repressing in ammation, inhibiting myocardial brosis and hypertrophy, and promoting tissue revascularization 22 . The genes within the blue module were enriched primarily in the PI3K-Akt signaling pathway and mitochondrial quality control.…”

Section: Discussionmentioning

confidence: 99%

Exploring the link between heart failure and cancer: insights into immune mechanisms and therapeutic targets for CD8 + T-cells

Zhou,

Pan,

et al. 2024

Preprint

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Background Heart failure (HF) is a terminal condition of multiple cardiovascular disorders. Cancer is a highly prevalent and deadly disease worldwide. However, the relationship between HF and cancer remains poorly understood. Therefore, there is a critical need to explore the potential mechanisms and therapeutic targets shared between HF and cancer. Method The Gene Expression Omnibus (GEO) database was used to download the RNA sequencing (RNA-seq) data of 356 patients, including individuals with HF and those without HF, to establish a co-expression network using the weighted correlation network analysis (WGCNA) algorithm, to calculate the compositions of immune infiltrating cells in the CIBERSORT algorithm, and to identify candidate hub genes within the modules of individuals with HF. Pearson Correlation Analysis was employed to identify the correlation between hub genes and CD8+T-cells in HF, as well as between hub genes and both tumor mutation burden (TMB) and microsatellite instability (MSI) across cancers. Molecular biology experiments were conducted to confirm the correlation between the hub genes and HF. Finally, the NetworkAnalyst database and the CellMiner database were utilized to predict the transcription factors (TFs) and potential therapeutic drugs of hub genes, respectively. Results HF was significantly linked to immune response pathway by the analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The brown and blue modules, identified by WGCNA, were the primary modules related to CD8+T-cells. Concomitantly, we observed a positive correlation between the expression levels of the four hub genes and the infiltration of CD8+T-cells in pan-cancer. Additionally, western blotting and real-time polymerase chain reaction (RT-PCR) validated the high expression of three hub genes (GZMM, NKG7, and ZAP70) in both mice and patients with HF compared to those in the control group. Finally, the hub gene-associated TF-gene networks and 11 agents targeting the hub genes were successfully predicted. Conclusion Our study highlights the shared pathogenesis of HF and cancer and provides valuable insights for developing novel therapeutic strategies that target shared pathways, offering new opportunities for improving the management and treatment outcomes of both HF and cancer.

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Section: Discussionmentioning

confidence: 99%

Exploring the link between heart failure and cancer: insights into immune mechanisms and therapeutic targets for CD8 + T-cells

Zhou,

Pan,

et al. 2024

Preprint

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“…The potential impact extends to various cellular processes, including cell survival, apoptosis, and differentiation, all of which are implicated in Notch signaling. The in ammation may compromise the integrated signaling network involving Notch-mediated crosstalk with pathways like Wnt and BMP during cardiac development, disrupting the coordinated regulation of cardiomyocyte fate [130].…”

Section: Impact Of This Damage On Switching Downstream Genes Transcri...mentioning

confidence: 99%

Investigating the Development and Progression of Myocarditis through the lens of the Genetic Architecture of Cardiomyocytes

Shafi,

Khan,

Virk

2024

Preprint

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Background: Myocarditis-induced inflammation disrupts the intricate genetic architecture governing cardiomyocyte development and function. Understanding the specific disruptions in key regulators, such as Isl1, Nkx2–5, GATA4, and signaling pathways like Wnt and BMPs, is crucial for unraveling the molecular underpinnings of cardiac dysfunction. This investigation holds paramount importance in informing targeted therapeutic strategies to mitigate inflammation-induced genetic disruptions, offering potential breakthroughs in the management of myocarditis and improving outcomes for affected individuals. Methods: Databases, including PubMed, MEDLINE, and Google Scholar, were searched for published articles without any date restrictions, focusing on cardiac genes, signaling pathways, and transcription factors, with an emphasis on NF-κB in myocarditis. This study adheres to relevant PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Results: This study reveals profound disruptions in the genetic architecture of cardiomyocytes. Transcriptional regulatory networks crucial for cardiomyocyte differentiation, including Isl1, Nkx2–5, GATA4, and Tbx5, exhibit altered expression patterns, suggesting compromised maturation processes. The Brg1/Baf60 – Smarcd3 complex, HAND1/2, and MYOCD, essential for cardiogenic regulation, are susceptible to inflammatory damage, impacting cell fate determination. NF-κB-mediated damage to BMPs and the Wnt-signaling pathway results in downstream shifts, affecting gene expression dynamics. These disruptions, coupled with compromised survival mechanisms and heightened apoptotic susceptibility, contribute to cardiac dysfunction and increased arrhythmogenic risk. Altered ECM remodeling and fibrosis further underscore the complexity of myocarditis-induced genetic alterations. Insights from these results hold implications for developing targeted therapeutic strategies aimed at mitigating inflammation-induced genetic disruptions and preserving cardiac health in the context of myocarditis. Conclusion: Myocarditis-induced inflammation disrupts the intricate genetic architecture of cardiomyocytes, compromising key regulators like Isl1, Brg1/Baf60 complex, Nkx2–5, GATA4, Tbx5, Mef2c, HAND1/2, MYOCD, MSX2, HOPX, Wnt signaling, Notch, FGF, and BMPs. This disruption leads to impaired cardiomyocyte differentiation, compromised survival mechanisms, dysregulated ECM remodeling, and heightened pro-inflammatory responses, collectively resulting in cardiac dysfunction and structural abnormalities. Targeted therapeutic interventions to mitigate inflammation-induced genetic disruptions are crucial for preserving optimal cardiac function in the challenging landscape of myocarditis.

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“…When overexpressed specifically in cardiomyocytes, Notch also improves cardiac function by reducing the formation of scars [ 28 ]. Notch signaling pathway as a potential target for therapeutic approaches has been recently discussed [ 29 ]. Functional screening of congenital heart disease risk loci shows that maml3 mutants can decrease cardiomyocyte proliferation through inhibition of Notch signaling [ 30 ], indicating that overexpression of maml3 may induce cardiomyocyte proliferation by activating Notch.…”

Section: Role Of Molecular Signalings In Heart Regenerationmentioning

confidence: 99%

Regeneration of the heart: from molecular mechanisms to clinical therapeutics

et al. 2023

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Heart injury such as myocardial infarction leads to cardiomyocyte loss, fibrotic tissue deposition, and scar formation. These changes reduce cardiac contractility, resulting in heart failure, which causes a huge public health burden. Military personnel, compared with civilians, is exposed to more stress, a risk factor for heart diseases, making cardiovascular health management and treatment innovation an important topic for military medicine. So far, medical intervention can slow down cardiovascular disease progression, but not yet induce heart regeneration. In the past decades, studies have focused on mechanisms underlying the regenerative capability of the heart and applicable approaches to reverse heart injury. Insights have emerged from studies in animal models and early clinical trials. Clinical interventions show the potential to reduce scar formation and enhance cardiomyocyte proliferation that counteracts the pathogenesis of heart disease. In this review, we discuss the signaling events controlling the regeneration of heart tissue and summarize current therapeutic approaches to promote heart regeneration after injury.

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The Role of the Notch Signaling Pathway in Recovery of Cardiac Function after Myocardial Infarction

Cited by 27 publications

References 67 publications

Exploring the link between heart failure and cancer: insights into immune mechanisms and therapeutic targets for CD8 + T-cells

Exploring the link between heart failure and cancer: insights into immune mechanisms and therapeutic targets for CD8 + T-cells

Investigating the Development and Progression of Myocarditis through the lens of the Genetic Architecture of Cardiomyocytes

Regeneration of the heart: from molecular mechanisms to clinical therapeutics

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