Cardiomyocyte S1pr1 regulates cardiac regeneration via AKT/mTOR signaling pathway
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PROVIDER: PRJNA1009408 | ENA |
REPOSITORIES: ENA
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Project description:Mammalian hearts had the capability to regenerate cardiomyocyte and completely recover after heart injury within a limited time window after birth. It has been shown that sphingosine 1-phospahte receptor 1 (S1pr1) was highly expressed in cardiomyocytes and played an important role in heart development and pathological cardiac remodeling. Herein, we aim to investigate the role of CM-S1pr1 for cardiac regeneration and tissue repair after heart injury. We generated cardiomyocyte (CM)-specific S1pr1 knock-out mice and showed that CM-specific S1pr1 loss-of-function significantly severely reduced cardiomyocyte proliferation and heart regeneration in neonatal mice after both apex resection and myocardial infarction, whereas S1pr1 gain-of-function by AAV9-mediated CM-specific overexpression of S1pr1 significantly boosted cardiac regeneration and improved cardiac functions after heart injuries. We next identified that S1pr1 activated AKT/mTOR/CyclinD1 and Bcl-2 signaling pathways, and thus promoted cardiomyocyte proliferation and inhibited CM apoptosis, respectively.Of note, we applied CM-targeted gene therapy by AAV9-cTNT to specifically overexpress S1pr1 in cardiomyocytes and achieved an efficient S1pr1 overexpression in CMs in vivo. This CM-targeted strategy to overexpress S1pr1 significantly enhanced cardiac regeneration and improved cardiac functions after myocardial infarction in an adult mouse model, suggesting a potential strategy to boost adult cardiac regeneration in vivo.
2024-08-01 | GSE241722 | GEO
Project description:For a short period of time in mammalian neonates, the mammalian heart can regenerate via cardiomyocyte proliferation. This regenerative capacity is largely absent in adults. In other organisms, including zebrafish, damaged hearts can regenerate throughout their lifespans. Many studies have been performed to understand the mechanisms of cardiomyocyte de-differentiation and proliferation during heart regeneration however, the underlying reason why adult zebrafish and young mammalian cardiomyocytes are primed to enter cell cycle have not been identified. Here we show the primed state of a pro-regenerative cardiomyocyte is dictated by its amino acid profile and metabolic state. Adult zebrafish cardiomyocyte regeneration is a result of amino acid-primed mTOR activation. Zebrafish and neonatal mouse cardiomyocytes display elevated glutamine levels, predisposing them to amino acid-driven activation of mTORC1. Injury initiates Wnt/β-catenin signalling that instigates primed mTORC1 activation, Lin28 expression and metabolic remodeling necessary for zebrafish cardiomyocyte regeneration. These studies reveal a unique mTORC1 primed state in zebrafish and mammalian regeneration competent cardiomyocytes.
2022-02-15 | PXD011791 | Pride
Project description:While glucose–lipid metabolic remodeling is a major driver of cardiomyocyte proliferative decline, the role of amino acid metabolism in cardiac generation remains poorly understood. Here, we identify glycine as a previously unrecognized pro-proliferative metabolic regulator in mammalian cardiomyocytes. Notably, exogenous glycine supplementation significantly enhanced cardiomyocyte proliferation in both neonatal and adult models, while also demonstrating enhanced efficacy in promoting cardiac repair following myocardial infarction. Mechanistically, glycine activated PI3K–AKT signaling through the amino acid sensor GCN2 and weakened the GCN2–AKT association, thereby facilitating AKT phosphorylation and enabling cardiomyocyte cell cycle re-entry. To address the pharmacokinetic limitations of free glycine administration, specifically its high peak concentration and suboptimal biodistribution profiles, we developed a cardiac-targeted liposomal nanoformulation (LNP@glycine) that exhibited enhanced myocardial accumulation efficacy, reduced dosing requirements, and further improved therapeutic efficacy. Collectively, our findings reveal glycine as a novel metabolic regulator of heart regeneration and highlight a translatable strategy that integrates amino acid-specific metabolic modulation with precision targeted delivery for ischemic heart disease.
2026-02-06 | GSE318305 | GEO
Project description: Not available
| S-EPMC11729560 | biostudies-literature
Project description:The mTOR (mammalian Target of Rapamycin) pathway is constitutively activated in Diffuse Large B-Cell Lymphoma (DLBCL). mTOR inhibition has been shown to have clinical activity in patients with DLBCL, although overall response rates remain low. We therefore evaluated differences in the transcriptome between DLBCL cell lines with differential sensitivity to the mTOR inhibitor Rapamycin, to (A) identify gene-expression patterns(GEP) capable of identifying sensitivity to Rapamycin, (B) understand the underlying mechanisms of resistance to Rapamycin in DLBCL and (C) identify bioactive molecules likely to synergize with mTOR inhibitors. Using Affymetrix HuGene ST 1.0 microarrays, we were able to identify a gene expression signature capable of accurately predicting sensitivity and resistance to Rapamycin in DLBCL cell lines. Pathway analysis identified the serine/threonine kinase Akt as central to the differentially-expressed gene network. Connectivity mapping of our datasets identified compounds targeting the AKT pathway with a high likelihood of reversing the GEP associated with resistance to Rapamycin. Specifically, we evaluated the HIV protease inhibitor (PI) Nelfinavir, which is known to have anti-cancer and Akt-inhibitory properties, as well as the small molecule Akt inhibitor MK-2206, for their potential to synergize with to Rapamycin in DLBCL. Nelfinavir and MK-2206 caused profound inhibition of cell viability in combination with Rapamycin in DLBCL cell lines. Low nanomolar concentrations of Rapamycin inhibited phosphorylation of Akt and also downstream targets of activated mTOR when used in combination with these Akt inhibitors. These findings have the potential to significantly improve patient selection for mTOR inhibitor therapy, and to improve rates and depths of response. More broadly, they support the use of global RNA expression and connectivity mapping to improve patient selection and identify synergistic drug combinations for cancer therapy. DLBCL cell lines were tested for Rapamycin sensitivity and classified as "sensitive" or "resistant." Genome-wide analysis of all cell lines were performed using the Affymetrix HuGene ST 1.0 Array Platform. Genes with differential expression between sensitive and resistant cell lines were analyzed using Statistical Analysis of Microarrays (SAM) software, and a signature of genes determnined. This signature was found to accurately predict sensitivity or resistance of other DLBCL cell lines, and to identify the protein kinase Akt as central to resistance.
2012-04-29 | E-GEOD-27255 | biostudies-arrayexpress
Project description:Glycine Promotes Cardiomyocyte Proliferation and Cardiac Regeneration via the GCN2/AKT Axis
| PRJNA1418579 | ENA
Project description:The mTOR (mammalian Target of Rapamycin) pathway is constitutively activated in Diffuse Large B-Cell Lymphoma (DLBCL). mTOR inhibition has been shown to have clinical activity in patients with DLBCL, although overall response rates remain low. We therefore evaluated differences in the transcriptome between DLBCL cell lines with differential sensitivity to the mTOR inhibitor Rapamycin, to (A) identify gene-expression patterns(GEP) capable of identifying sensitivity to Rapamycin, (B) understand the underlying mechanisms of resistance to Rapamycin in DLBCL and (C) identify bioactive molecules likely to synergize with mTOR inhibitors. Using Affymetrix HuGene ST 1.0 microarrays, we were able to identify a gene expression signature capable of accurately predicting sensitivity and resistance to Rapamycin in DLBCL cell lines. Pathway analysis identified the serine/threonine kinase Akt as central to the differentially-expressed gene network. Connectivity mapping of our datasets identified compounds targeting the AKT pathway with a high likelihood of reversing the GEP associated with resistance to Rapamycin. Specifically, we evaluated the HIV protease inhibitor (PI) Nelfinavir, which is known to have anti-cancer and Akt-inhibitory properties, as well as the small molecule Akt inhibitor MK-2206, for their potential to synergize with to Rapamycin in DLBCL. Nelfinavir and MK-2206 caused profound inhibition of cell viability in combination with Rapamycin in DLBCL cell lines. Low nanomolar concentrations of Rapamycin inhibited phosphorylation of Akt and also downstream targets of activated mTOR when used in combination with these Akt inhibitors. These findings have the potential to significantly improve patient selection for mTOR inhibitor therapy, and to improve rates and depths of response. More broadly, they support the use of global RNA expression and connectivity mapping to improve patient selection and identify synergistic drug combinations for cancer therapy.
2012-04-30 | GSE27255 | 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:To investigate the functional and mechanistic roles of mTOR in zebrafish larvae fin regeneration, we firstly examined the spatiotemporal expression of mTOR in larvae fin and established a mTOR knockout (mTOR-KO) transgenic fish line using CRISPER / Cas9 gene editing technology. Moreover, mTOR was essential for the activation of macrophages, which is a key factor in maintaining the regenerative repair process. We also demonstrated that mTOR knockdown attenuated the proliferative capacity of bud embryo cell during the regenerative phase, while cell apoptosis was not affected. RNA-sequence analysis showed changes in mitochondrial function and dnm1l was identified as the main regulatory factor during the fin regeneration stage. We further suggested that mTOR may promote mitochondrial fission to support bud embryo cell regeneration via CaM-mTOR-dnm1l axis.
2023-10-13 | GSE242949 | GEO
Project description:Ischemic heart disease remains a leading cause of mortality, with limited adult cardiac regeneration due to insufficient cardiomyocyte proliferation. This study investigates the role of Growth Arrest-Specific Gene 6 (Gas6) in regulating cardiomyocyte cell cycle and promoting cardiac repair. Gas6 expression declines postnatally in cardiomyocytes but increases during neonatal heart regeneration following myocardial infarction (MI). Cardiomyocyte-specific Gas6 knockout (Gas6CKO) mice exhibited reduced cardiomyocyte proliferation, decreased total cardiomyocyte numbers, and delayed-onset heart failure with ventricular dilation by ~250 days, as confirmed by transcriptomic analysis revealing downregulation of cell cycle pathways and upregulation of fibrotic and contractile genes in Gas6CKO versus control hearts at 250 days. Conversely, AAV9-mediated cardiomyocyte-specific Gas6 overexpression enhanced neonatal cardiomyocyte proliferation, dedifferentiation, and hyperplastic growth, while in adult MI models, it improved cardiac function, reduced infarct size, and increased proliferative markers (Ki67, pH3, Aurora B) in the border zone. Bulk RNA-sequencing of primary mouse cardiomyocytes overexpressing Ad-Gas6 versus controls identified upregulated cell cycle and mitotic pathways, alongside downregulated cardiac contraction and extracellular matrix organization, with transcription factor enrichment highlighting Yap-mediated activation via TEAD2 and E2F1. Mechanistically, Gas6 binds Sav1 to disrupt the Sav1-Mst1 complex, inhibiting Hippo pathway phosphorylation, promoting Yap nuclear translocation, and driving cell cycle gene expression. These findings position Gas6 as a therapeutic target for cardiac regeneration in ischemic heart disease.
2026-08-21 | GSE306068 | GEO