Exploring the therapeutic potential of cellular senescence for cardiac fibrosis

• Applicant: Kathleen Meyer, Ph.D.
• 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