E2f1 Overexpression Reduces Aging-Associated DNA Damage in Cultured Cerebral Endothelial Cells and Improves Cognitive Performance in Aged Mice

Authors

Sheelu Monga
Samantha Flores
Maria Pilar Blasco-Conesa
Syed M Rahman
Brian Noh
Pedram Peesh
Bhanu Priya Ganesh
Sean P Marrelli
Louise D McCullough
Jose Felix Moruno-Manchon

Language

English

Publication Date

1-1-2025

Journal

Oxidative Medicine and Cellular Longevity

DOI

10.1155/omcl/3242282

PMID

40761766

PMCID

PMC12321429

PubMedCentral® Posted Date

7-28-2025

PubMedCentral® Full Text Version

Post-print

Abstract

As we age, cerebral endothelial cells (CECs) are less efficient in maintaining genome integrity and accumulate DNA damage. DNA damage in the brain endothelium can lead to the impairment of the blood–brain barrier (BBB), which is a major factor in brain dysfunction and dementia. Thus, identifying factors that regulate DNA repair in the brain endothelium can prevent brain dysfunction associated with aging. E2F1 is a transcription factor that regulates the expression of genes associated with DNA repair, among other functions. We hypothesize that E2F1 is downregulated in the brain vasculature of mice with aging and that E2F1 upregulation can improve cognitive function. We found that in the brain endothelium, E2F1 was significantly less phosphorylated, which is associated with its transcriptional activity, in the brain vasculature of aged mice and cultured CEC derived from aged mice compared with those from young mice. We found that E2f1 overexpression reduced DNA damage in cultured CEC, and targeting the brain vasculature to overexpress E2f1 improved cognition and increased the expression of genes associated with BBB integrity in aged mice. From RNA sequencing data from cultured CEC, we found that E2f1 overexpression significantly upregulated Acod1, which codes for aconitate decarboxylase-1 (ACOD1), an enzyme that produces itaconate. We also found that 4-octyl itaconate (4-OI), a derivative of itaconate, reduced DNA damage, promoted cell proliferation, and restored endothelial barrier function from oxidative stress in cultured CEC. Thus, our study identifies the E2F1-ACOD1 axis as a molecular pathway that can protect the brain endothelium from oxidative stress and aging.

Keywords

Animals, DNA Damage, E2F1 Transcription Factor, Endothelial Cells, Mice, Aging, Cognition, Brain, Male, Cells, Cultured, Mice, Inbred C57BL, Oxidative Stress, Blood-Brain Barrier, aging, cognition, DNA damage, E2F1, endothelial cells, itaconate

Published Open-Access

yes

Recommended Citation

Monga, Sheelu; Flores, Samantha; Blasco-Conesa, Maria Pilar; et al., "E2f1 Overexpression Reduces Aging-Associated DNA Damage in Cultured Cerebral Endothelial Cells and Improves Cognitive Performance in Aged Mice" (2025). Faculty, Staff and Student Publications. 5700.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5700