Aging Is Associated With Impaired Activation of Protein Homeostasis-Related Pathways After Cardiac Arrest in Mice.

Published

Journal Article

Background The mechanisms underlying worse outcome at advanced age after cardiac arrest ( CA ) and resuscitation are not well understood. Because protein homeostasis (proteostasis) is essential for cellular and organismal health, but is impaired after CA , we investigated the effects of age on proteostasis-related prosurvival pathways activated after CA . Methods and Results Young (2-3 months old) and aged (21-22 months old) male C57Bl/6 mice were subjected to CA and cardiopulmonary resuscitation ( CPR ). Functional outcome and organ damage were evaluated by assessing neurologic deficits, histological features, and creatinine level. CA / CPR -related changes in small ubiquitin-like modifier conjugation, ubiquitination, and the unfolded protein response were analyzed by measuring mRNA and protein levels in the brain, kidney, and spinal cord. Thiamet-G was used to increase O-linked β-N-acetylglucosamine modification. After CA / CPR , aged mice had trended lower survival rates, more severe tissue damage in the brain and kidney, and poorer recovery of neurologic function compared with young mice. Furthermore, small ubiquitin-like modifier conjugation, ubiquitination, unfolded protein response, and O-linked β-N-acetylglucosamine modification were activated after CA / CPR in young mice, but their activation was impaired in aged mice. Finally, pharmacologically increasing O-linked β-N-acetylglucosamine modification after CA improved outcome. Conclusions Results suggest that impaired activation of prosurvival pathways contributes to worse outcome after CA / CPR in aged mice because restoration of proteostasis is critical to the survival of cells stressed by ischemia. Therefore, a pharmacologic intervention that targets aging-related impairment of proteostasis-related pathways after CA / CPR may represent a promising therapeutic strategy.

Full Text

Duke Authors

Cited Authors

  • Shen, Y; Yan, B; Zhao, Q; Wang, Z; Wu, J; Ren, J; Wang, W; Yu, S; Sheng, H; Crowley, SD; Ding, F; Paschen, W; Yang, W

Published Date

  • September 4, 2018

Published In

Volume / Issue

  • 7 / 17

Start / End Page

  • e009634 -

PubMed ID

  • 30371162

Pubmed Central ID

  • 30371162

Electronic International Standard Serial Number (EISSN)

  • 2047-9980

Digital Object Identifier (DOI)

  • 10.1161/JAHA.118.009634

Language

  • eng

Conference Location

  • England