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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Nov 10, 2022 |
| Title |
Targeting cardiomyocyte ADAM10 ectodomain shedding promotes survival early after myocardial infarction |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
Comparative gene expression profiling analysis of RNA-seq data for mouse hearts of ADAM10 inhibitor (A10i = GI254023X)-treated (samples A116, A117, A119, A120) and DMSO-treated control mice (samples A105, A127, A128, A129) 3d after infarction via LAD ligation.
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| Contributor(s) |
Klapproth E, El-Armouche A |
| Citation(s) |
36496449 |
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| Submission date |
Nov 04, 2022 |
| Last update date |
Jan 05, 2023 |
| Contact name |
Erik Klapproth |
| E-mail(s) |
erik.klapproth@tu-dresden.de
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| Organization name |
Technische Universität Dresden
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| Department |
Institute of Pharmacology and Toxicology
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| Street address |
Fiedlerstraße 42
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| City |
Dresden |
| ZIP/Postal code |
01307 |
| Country |
Germany |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (11)
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| GSM6710248 |
C57BL/6J mouse heart, A10i, A119 |
| GSM6710249 |
C57BL/6J mouse heart, A10i, A120 |
| GSM6710250 |
C57BL/6J mouse heart, DMSO, A127 |
| GSM6710251 |
C57BL/6J mouse heart, DMSO, A128 |
| GSM6710252 |
C57BL/6J mouse heart, DMSO, A129 |
| GSM6710253 |
C57BL/6J mouse heart, Sham, S1 |
| GSM6710254 |
C57BL/6J mouse heart, Sham, S2 |
| GSM6710255 |
C57BL/6J mouse heart, Sham, S3 |
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| Relations |
| BioProject |
PRJNA898315 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE217268_bfx1704.mm10.e98.tsv.gz |
4.2 Mb |
(ftp)(http) |
TSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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