Senolytics and Senomorphics Targeting p38MAPK/NF-κB Pathway Protect Endothelial Cells from Oxidative Stress-Mediated Premature Senescence

Ya, Jingyuan; Bayraktutan, Ulvi

Abstract

Oxidative stress is a prominent causal factor in the premature senescence of microvascular endothelial cells and the ensuing blood–brain barrier (BBB) dysfunction. Through the exposure of an in vitro model of human BBB, composed of brain microvascular endothelial cells (BMECs), astrocytes, and pericytes to H2O2, this study examined whether a specific targeting of the p38MAPK/NF-κB pathway and/or senescent cells could delay oxidative stress-mediated EC senescence and protect the BBB. Enlarged BMECs, displaying higher β-galactosidase activity, γH2AX staining, p16 expression, and impaired tubulogenic capacity, were regarded as senescent. The BBB established with senescent BMECs had reduced transendothelial electrical resistance and increased paracellular flux, which are markers of BBB integrity and function, respectively. Premature senescence disrupted plasma-membrane localization of the tight junction protein, zonula occludens-1, and elevated basement membrane-degrading matrix metalloproteinase-2 activity and pro-inflammatory cytokine release. Inhibition of p38MAPK by BIRB796 and NF-κB by QNZ and the elimination of senescent cells by a combination of dasatinib and quercetin attenuated the effects of H2O2 on senescence markers; suppressed release of the pro-inflammatory cytokines interleukin-8, monocyte chemoattractant protein-1, and intercellular adhesion molecule-1; restored tight junctional unity; and improved BBB function. In conclusion, therapeutic approaches that mitigate p38MAPK/NF-κB activity and senescent cell accumulation in the cerebrovasculature may successfully protect BBB from oxidative stress-induced BBB dysfunction.

Citation

Ya, J., & Bayraktutan, U. (2024). Senolytics and Senomorphics Targeting p38MAPK/NF-κB Pathway Protect Endothelial Cells from Oxidative Stress-Mediated Premature Senescence. Cells, 13(15), Article 1292. https://doi.org/10.3390/cells13151292

• Journal Article Type: Article
• Acceptance Date: Jul 28, 2024
• Online Publication Date: Jul 31, 2024
• Publication Date: 2024-08
• Deposit Date: Aug 2, 2024
• Publicly Available Date: Aug 2, 2024
• Journal: Cells
• Electronic ISSN: 2073-4409
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 13
• Issue: 15
• Article Number: 1292
• DOI: https://doi.org/10.3390/cells13151292
• Keywords: endothelial cell; senescence; p38MAPK; NF-κB; blood-brain barrier; senotherapeutic; senolytic; senomorphic; aging; age
• Public URL: https://nottingham-repository.worktribe.com/output/37930468