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Exploring the therapeutic potential of cellular senescence for cardiac fibrosis

Subject Area Cardiology, Angiology
Pharmacology
Cell Biology
Term from 2017 to 2020
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 379092936
 
Final Report Year 2020

Final Report Abstract

Here, I compare the two best described first-generation senolytic agents, namely navitoclax and the drug cocktail dasatinib + quercetin (D+Q), in fibrotic acute and chronic renal disease. The analysis of the acute kidney injury model (one intraperitoneal injection of folic acid, 250mg/kg) indicates different therapeutic effects of these interventions. Both senolytic treatments showed a reduction in senescent epithelial and interstitial cells based on quantitative assessment of the senescence marker senescence-associated beta-galactosidase (SA-ß-GAL) as well as p21. However, navitoclax did not improve the disease outcome whereas D+Q remarkably improved renal morphology, fibrosis and function upon AKI induction. In vitro, I observed that navitoclax, but not D+Q robustly kills senescent renal epithelial cells (the main senescent renal cell type upon AKI). I show an alternative mechanism by which D+Q diminishes senescent cells in vivo and improves the disease outcome. I propose that D+Q impacts on immune cells towards a general anti-inflammatory (senomorphic) effect that would reduce the damage and thus, senescent cells and fibrosis.

Publications

  • Cardiac myocyte hypertrophy triggers premature senescence of cardiac myofibroblasts. (Naunyn-Schmiedeberg´s Arch Pharmacol (2017) 390 (Suppl 1: S1–S101)
    Meyer K, Ognenoska I Ramanujam D., Engelhardt S, Sarikas A
  • Cardiac myocyte hypertrophy triggers premature senescence of cardiac myofibroblasts. International Cell Senescence Association (Clin Res Cardiol 106, Suppl 1, 2017)
    Meyer K, Ramanujam D, Ognenoska I., Engelhardt S, Sarikas A
  • Cardiac myocyte hypertrophy triggers premature senescence of cardiac myofibroblasts. International Cell Senescence Association. International cellular senescence association, annual meeting; Paris, 2017
    Meyer K, Ognenoska I Ramanujam D., Engelhardt S, Sarikas A
  • Senescence in the heart. Spanish Network Of Cellular Senescence. Spanish senescence association; Madrid, 2017
    Meyer K, Ramanujam D, Ognenoska I., Engelhardt S, Sarikas A
  • Differential effects of Navitoclax and Dasatinib/Quercetin on acute kidney injury (AKI). International cellular senescence association, annual meeting; Athens, 2019
    Meyer K, Liao C, Chaib S, Chondronasiou D, Prats N, Aguilera M, Schmitt R, Melk A, Maria del Mar García, Serrano M
 
 

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