EA.hy926 Cells and HUVECs Share Similar Senescence Phenotypes but Respond Differently to the Senolytic Drug ABT-263

Ibrahim Y. Abdelgawad, Kevin Agostinucci, Somia G. Ismail, Marianne K.O. Grant, Beshay N. Zordoky

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Doxorubicin (DOX) induces endothelial cell (EC) senescence, which contributes to endothelial dysfunction and cardiovascular complications. Senolytic drugs selectively eliminate senescent cells to ameliorate senescence-mediated pathologies. Previous studies have demonstrated differences between immortalized and primary EC models in some characteristics. However, the response of DOX-induced senescent ECs to senolytics has not been determined across these two models. In the present work, we first established a comparative characterization of DOX-induced senescence phenotypes in immortalized EA.hy926 endothelial-derived cells and primary human umbilical vein EC (HUVECs). Thereafter, we evaluated the senolytic activity of four senolytics across both ECs. Following the DOX treatment, both EA.hy926 and HUVECs shared similar senescence phenotypes characterized by upregulated senescence markers, increased SA-β-gal activity, cell cycle arrest, and elevated expression of the senescence-associated secretory phenotype (SASP). The potentially senolytic drugs dasatinib, quercetin, and fisetin demonstrated a lack of selectivity against DOX-induced senescent EA.hy926 cells and HUVECs. However, ABT-263 (Navitoclax) selectively induced the apoptosis of DOX-induced senescent HUVECs but not EA.hy926 cells. Mechanistically, DOX-treated EA.hy926 cells and HUVECs demonstrated differential expression levels of the BCL- 2 family proteins. In conclusion, both EA.hy926 cells and HUVECs demonstrate similar DOX-induced senescence phenotypes but they respond differently to ABT-263, presumably due to the different expression levels of BCL-2 family proteins.

Original languageEnglish (US)
Article number1992
JournalCells
Volume11
Issue number13
DOIs
StatePublished - Jul 1 2022

Bibliographical note

Funding Information:
This research is supported by the National Heart, Lung, and Blood Institute, grant R01HL151740. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. I.Y.A. is supported by the Bighley Graduate Fellowship from the College of Pharmacy, University of Minnesota.

Funding Information:
Funding: This research is supported by the National Heart, Lung, and Blood Institute, grant R01HL151740. The content is solely the responsibility of the authors and does not necessarily rep‐ resent the official views of the National Institutes of Health. I.Y.A. is supported by the Bighley Grad‐ uate Fellowship from the College of Pharmacy, University of Minnesota.

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • ABT-263
  • BCL-2 family
  • doxorubicin
  • endothelial cells
  • senescence
  • senolytics

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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