Aging Is Associated With Impaired Activation of Protein Homeostasis-Related Pathways After Cardiac Arrest in Mice.
Abstract
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.
Type
Journal articleSubject
KidneyBrain
Spinal Cord
Animals
Mice
Heart Arrest
Acetylglucosamine
Small Ubiquitin-Related Modifier Proteins
Cardiopulmonary Resuscitation
Recovery of Function
Aging
Ubiquitination
Unfolded Protein Response
Proteostasis
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https://hdl.handle.net/10161/23246Published Version (Please cite this version)
10.1161/jaha.118.009634Publication Info
Shen, Yuntian; Yan, Baihui; Zhao, Qiang; Wang, Zhuoran; Wu, Jiangbo; Ren, Jiafa; ...
Yang, Wei (2018). Aging Is Associated With Impaired Activation of Protein Homeostasis-Related Pathways
After Cardiac Arrest in Mice. Journal of the American Heart Association, 7(17). pp. e009634. 10.1161/jaha.118.009634. Retrieved from https://hdl.handle.net/10161/23246.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Wulf Paschen
Professor in Anesthesiology
My research interests are understanding the mechanisms underlying induction of cell
death induced by a severe form of cellular stress. I am particularly interested in
the role of the endoplasmic reticulum in the pathological process induced by transient
cerebral ischemia and culminating in neuronal cell death. This pathological process
is associated with an irreversible suppression of protein synthese that limits the
ability of cells to withstand ischemia-induced impairment of endoplasmic r
Huaxin Sheng
Associate Professor in Anesthesiology
We have successfully developed various rodent models of brain and spinal cord injuries
in our lab, such as focal cerebral ischemia, global cerebral ischemia, head trauma,
subarachnoid hemorrhage, intracerebral hemorrhage, spinal cord ischemia and compression
injury. We also established cardiac arrest and hemorrhagic shock models for studying
multiple organ dysfunction. Our current studies focus on two projects. One is to
examine the efficacy of catalytic antioxidant in treating cerebral is
Wei Yang
Associate Professor in Anesthesiology
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