PUBLICATION

Selective CDK9 inhibition resolves neutrophilic inflammation and enhances cardiac regeneration in larval zebrafish

Authors
Kaveh, A., Bruton, F.A., Oremek, M.E.M., Tucker, C.S., Taylor, J.M., Mullins, J.J., Rossi, A.G., Denvir, M.A.
ID
ZDB-PUB-210916-8
Date
2021
Source
Development (Cambridge, England)   149(8): (Journal)
Registered Authors
Mullins, John, Rossi, Adriano
Keywords
AT7519, Cardiac, Neutrophil, Regeneration, Resolution, Zebrafish
MeSH Terms
  • Zebrafish Proteins/antagonists & inhibitors*
  • Zebrafish Proteins/metabolism
  • Animals
  • Zebrafish
  • Cyclin-Dependent Kinase 9/antagonists & inhibitors*
  • Cyclin-Dependent Kinase 9/metabolism
  • Myocardium/enzymology*
  • Neutrophils/enzymology*
  • Flavonoids/pharmacology*
  • Piperidines/pharmacology*
  • Inflammation/drug therapy
  • Inflammation/enzymology
  • Pyrazoles/pharmacology*
  • Regeneration/drug effects*
(all 14)
PubMed
34523672 Full text @ Development
Abstract
Sustained neutrophilic inflammation is detrimental for cardiac repair and associated with adverse outcomes following myocardial infarction (MI). An attractive therapeutic strategy to treat MI is to reduce or remove infiltrating neutrophils to promote downstream reparative mechanisms. CDK9 inhibitor compounds enhance the resolution of neutrophilic inflammation, however, their effects on cardiac repair/regeneration are unknown. Our laboratory has devised a cardiac injury model to investigate inflammatory and regenerative responses in larval zebrafish using heartbeat-synchronised light sheet fluorescence microscopy. We used this model to test two clinically approved CDK9 inhibitors, AT7519 and Flavopiridol, examining their effects on neutrophils, macrophages and cardiomyocyte regeneration. We found AT7519 and Flavopiridol resolve neutrophil infiltration by inducing reverse migration from the cardiac lesion. While continuous exposure to AT7519 or Flavopiridol caused adverse phenotypes, transient treatment accelerated neutrophil resolution while avoiding these effects. Transient treatment with AT7519, but not Flavopiridol, augmented wound-associated macrophage polarisation, which enhanced macrophage-dependent cardiomyocyte number expansion and the rate of myocardial wound closure. Using cdk9-/- knockout mutants we showed AT7519 is a selective CDK9 inhibitor, revealing the potential of such treatments to promote cardiac repair/regeneration.
Genes / Markers
Figures
Figure Gallery (6 images)
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Expression
No data available
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ed9
    		Small Deletion
    f2TgTransgenic Insertion
      gl23TgTransgenic Insertion
        sa43296
          		Point Mutation
          st95
            		Small Deletion
            twu26TgTransgenic Insertion
              uwm7TgTransgenic Insertion
                zf52TgTransgenic Insertion
                  1 - 8 of 8
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                  Human Disease / Model
                  No data available
                  Sequence Targeting Reagents
                  No data available
                  Fish
                  No data available
                  Antibodies
                  No data available
                  Orthology
                  No data available
                  Engineered Foreign Genes
                  Marker Marker Type Name
                  DsRed2EFGDsRed2
                  EGFPEFGEGFP
                  GFPEFGGFP
                  mCherryEFGmCherry
                  1 - 4 of 4
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                  Mapping
                  No data available
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                  Citation
                  Kaveh, A., Bruton, F.A., Oremek, M.E.M., Tucker, C.S., Taylor, J.M., Mullins, J.J., Rossi, A.G., Denvir, M.A. (2021) Selective CDK9 inhibition resolves neutrophilic inflammation and enhances cardiac regeneration in larval zebrafish. Development (Cambridge, England). 149(8):.