Activation of the ATF6 (Activating Transcription Factor 6) Signaling Pathway in Neurons Improves Outcome After Cardiac Arrest in Mice

Autor: Qiang Zhao, Shu Yu, Yuntian Shen, Zhuoran Wang, Ran Li, Huaxin Sheng, Wei Yang
Rok vydání: 2021
Předmět:
Resuscitation
Activating transcription factor
Mice
Transgenic
transgenic mice
Neuroprotection
Resuscitation Science
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
Ischemia
Medicine
Animals
RNA‐Seq
Gene Knock-In Techniques
030304 developmental biology
Original Research
Neurons
0303 health sciences
Behavior
Animal
ATF6
business.industry
Endoplasmic reticulum
Ubiquitination
Brain
brain ischemia
Cell biology
Activating Transcription Factor 6
Heart Arrest
Mice
Inbred C57BL
Disease Models
Animal
Proteostasis
Neuroprotective Agents
ER‐associated degradation
Reperfusion Injury
Unfolded protein response
Unfolded Protein Response
neuroprotection
Signal transduction
Cardiology and Cardiovascular Medicine
business
ER stress
030217 neurology & neurosurgery
Basic Science Research
Signal Transduction
Zdroj: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
ISSN: 2047-9980
Popis: Background Ischemia/reperfusion injury impairs proteostasis, and triggers adaptive cellular responses, such as the unfolded protein response (UPR), which functions to restore endoplasmic reticulum homeostasis. After cardiac arrest (CA) and resuscitation, the UPR is activated in various organs including the brain. However, the role of the UPR in CA has remained largely unknown. Here we aimed to investigate effects of activation of the ATF6 (activating transcription factor 6) UPR branch in CA. Methods and Results Conditional and inducible sATF6‐KI (short‐form ATF6 knock‐in) mice and a selective ATF6 pathway activator 147 were used. CA was induced in mice by KCl injection, followed by cardiopulmonary resuscitation. We first found that neurologic function was significantly improved, and neuronal damage was mitigated after the ATF6 pathway was activated in neurons of sATF6‐KI mice subjected to CA/cardiopulmonary resuscitation. Further RNA sequencing analysis indicated that such beneficial effects were likely attributable to increased expression of pro‐proteostatic genes regulated by ATF6. Especially, key components of the endoplasmic reticulum–associated degradation process, which clears potentially toxic unfolded/misfolded proteins in the endoplasmic reticulum, were upregulated in the sATF6‐KI brain. Accordingly, the CA‐induced increase in K48‐linked polyubiquitin in the brain was higher in sATF6‐KI mice relative to control mice. Finally, CA outcome, including the survival rate, was significantly improved in mice treated with compound 147. Conclusions This is the first experimental study to determine the role of the ATF6 UPR branch in CA outcome. Our data indicate that the ATF6 UPR branch is a prosurvival pathway and may be considered as a therapeutic target for CA.
Databáze: OpenAIRE
Externí odkaz: