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Targeting cardiomyocyte ADAM10 ectodomain shedding promotes survival early after myocardial infarction

ABSTRACT: Targeting cardiomyocyte ADAM10 ectodomain shedding promotes survival early after myocardial infarction

PROVIDER: PRJNA898315 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22191550_1.fastq.gz	Fastqsanger.gz
	SRR22191550_2.fastq.gz	Fastqsanger.gz
	SRR22191551_1.fastq.gz	Fastqsanger.gz
	SRR22191551_2.fastq.gz	Fastqsanger.gz
	SRR22191552_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Targeting cardiomyocyte ADAM10 ectodomain shedding promotes survival early after myocardial infarction

Project description:Myocardial infarction (MI) contributes to cardiac mortality and morbidity. After myocardial infarction the innate immune response is pivotal in clearing of tissue debris as well as scar formation, but exaggerated cytokine and chemokine secretion with subsequent leukocyte infiltration also leads to further tissue damage. Post-translational regulation of cytokine / chemokine signaling occurs via ectodomain shedding through a disintegrin and metalloproteases (ADAMs). Here, we address the value of targeting a previously unknown ADAM10 / CX3CL1 axis in the regulation of neutrophil recruitment early after MI. We show that myocardial ADAM10 is distinctly upregulated in biopsies from patients with ischemia-driven cardiomyopathy and correlates with heart failure progression. Intriguingly, upon MI in mice, pharmacological treatment with the ADAM10 inhibitionor GI254023X as well as genetic cardiomycyte-specific ADAM10 deletion improves survival with markedly enhanced heart function and reduced scar size. Mechanistically, this is driven by abolished ADAM10-mediated CX3CL1 ectodomain shedding followed by diminished IL-1β-dependent inflammation, reduced neutrophil bone marrow egress as well as myocardial tissue infiltration. Genetic cardiomycyte-specific ADAM10 deletion confirmes the small-molecule data and leads to improved cardiac function and reduction in inflammatory markers after ischemic myocardial injury. Thus, our data shows a conceptual insight into how acute MI induces chemotactic signaling via ectodomain shedding in cardiomyocytes.

2022-11-10 | GSE217268 | GEO

Degradome of soluble ADAM10 and ADAM17 metalloproteases

Project description:Disintegrin and metalloproteinases ADAM10 and ADAM17 can release the extracellular region of a variety of membrane-bound proteins including cytokines, adhesion molecules, growth factors and receptors, important for many biological functions (ectodomain shedding).. So far, substrate identification for ADAM10 and ADAM17 focused exclusively on their membrane-anchored forms and their function as sheddases. With ADAM8 we now describe the first protease capable of releasing the ADAM17 ectodomain. Based on these findings, we investigated whether the soluble ectodomains of ADAM10 and ADAM17 still exhibit shedding activity and to determine their soluble protein substrate pool . To address this, a mass spectrometry-based N-terminomics approach (TAILS) was used to identify potential targets of soluble ADAM10 and ADAM17 (sADAM10/17) within the secretome of the murine cardiomyocyte cell line HL-1. We identified almost 140 protein cleavage events in total and 45 common substrates for both sADAM10 and sADAM17. Further in-vitro studies confirmed fibronectin, cystatin C, sN-cadherin, PCPE-1 as well as sAPP as direct substrates of soluble ADAM10 and/or ADAM17. Overall, we present the first degradome study for sADAM10 and sADAM17, thereby introducing a new regulation mode of the proteolytic activity of these essential proteases within the protease web.

2019-06-24 | PXD013718 | Pride

Targeting cardiomyocyte ADAM10 ectodomain shedding promotes survival early after myocardial infarction.

Project description:After myocardial infarction the innate immune response is pivotal in clearing of tissue debris as well as scar formation, but exaggerated cytokine and chemokine secretion with subsequent leukocyte infiltration also leads to further tissue damage. Here, we address the value of targeting a previously unknown a disintegrin and metalloprotease 10 (ADAM10)/CX3CL1 axis in the regulation of neutrophil recruitment early after MI. We show that myocardial ADAM10 is distinctly upregulated in myocardial biopsies from patients with ischemia-driven cardiomyopathy. Intriguingly, upon MI in mice, pharmacological ADAM10 inhibition as well as genetic cardiomycyte-specific ADAM10 deletion improves survival with markedly enhanced heart function and reduced scar size. Mechanistically, abolished ADAM10-mediated CX3CL1 ectodomain shedding leads to diminished IL-1β-dependent inflammation, reduced neutrophil bone marrow egress as well as myocardial tissue infiltration. Thus, our data shows a conceptual insight into how acute MI induces chemotactic signaling via ectodomain shedding in cardiomyocytes.

| S-EPMC9741599 | biostudies-literature

α-Ketoglutarate Promotes Cardiomyocyte Proliferation and Heart Regeneration after Myocardial Infarction

Project description:The neonatal mammalian heart is capable of substantial regeneration following injury through cardiomyocyte proliferation. However, this regenerative capacity is lost by postnatal (P) day 7. How to stimulate the adult cardiomyocyte to re-enter the cell cycle is still unknown. Accumulating evidence suggests that cardiomyocyte proliferation depends on its metabolic state. Due to the tight connection between the tricarboxylic acid cycle (TCA) and cell proliferation, we analyzed the TCA metabolites between P0.5 and P7 mouse hearts and found that α-ketoglutarate (α-KG) ranked first among the decreased metabolites. The intraperitoneal injection of exogenous α-KG extended the window of cardiomyocyte proliferation during heart development and promoted heart regeneration after myocardial infarction (MI) by inducing adult cardiomyocyte proliferation. This was confirmed in Ogdh-siRNA-treated mice with increased α-KG levels. Mechanistically, α-KG activates Jmjd3, a histone lysine demethylase, that decreases H3K27me3 expression and deposition of H3K4me3 at the promoters of cell cycle and structural maturation genes in cardiomyocytes. Our present study shows that α-KG promotes cardiomyocyte proliferation by Jmjd3-dependent demethylation and inactivation of H3K27me3 andH3K4me3, which is a potential therapeutic approach for treating MI and heart failure.

2024-07-12 | GSE272104 | GEO

α-Ketoglutarate Promotes Cardiomyocyte Proliferation and Heart Regeneration after Myocardial Infarction

Project description:α-Ketoglutarate Promotes Cardiomyocyte Proliferation and Heart Regeneration after Myocardial Infarction

| PRJNA1135118 | ENA

System-wide vitreous proteome dissection reveals impaired sheddase activity in diabetic retinopathy

Project description:Diabetic retinopathy (DR) is a major complication of diabetes mellitus causing significant vision loss. Despite the success of anti-VEGF therapy as an effective therapy, many DR patients do not respond well to the treatment, emphasizing the involvement of other molecular players. To unveil these, we performed deep vitreous proteome profiling of patients with proliferative DR and extracted aberrated protein networks. This revealed impairment in ectodomain shedding of several transmembrane proteins playing critical roles in neurodegeneration and angiogenesis, that pointed to defects in their regulating sheddases, particularly ADAM10, which emerged as the predominant sheddase. We confirmed that ADAM10 protease activity was reduced in ocular disease models and established that activation of ADAM10 can suppress endothelial cell activation and angiogenesis. Furthermore, we identified impaired ADAM10-AXL axis as a retinal angiogenic driver. Taken together, we demonstrate restoration of aberrant ectodomain shedding as an effective strategy for treating DR and propose ADAM10 as an attractive novel target.

2022-10-14 | PXD036033 | Pride

Cell-autonomous FLT3L shedding via ADAM10 mediates conventional dendritic cell development in mouse spleen

Project description:Cell-autonomous FLT3L shedding via ADAM10 mediates conventional dendritic cell development in mouse spleen

| PRJNA543088 | ENA

Expression data from Adam10 knock out mice and wild type

Project description:Adam10, a cell surface protease, cleaving many proteins including TNF-alpha and E-cadherin. Here we investigate the genome wide effects of Adam10 knock out on the transcriptome. Commercial microarrays (Affymetrix Mouse Gene ST 1.0) were used to generate genome wide mRNA profiles. Mouse tissue samples from n=4 wiltype skin and n=4 Adam10 knockout skin were used in the study.

2011-01-06 | E-GEOD-25480 | biostudies-arrayexpress

Inhibition of DYRK1A promotes cardiomyocyte proliferation and heart repair after myocardial infarction

Project description:Inhibition of DYRK1A promotes cardiomyocyte proliferation and heart repair after myocardial infarction

| PRJNA834827 | ENA

RNA-seq of cardiac-specific Cdk1 knockout mice at 3 weeks after experimental myocardial infarction

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

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