PDK4 Decrease Neuronal Apoptosis via Inhibiting ROS-ASK1/P38 Pathway in Early Brain Injury After Subarachnoid Hemorrhage.
Antioxid Redox Signal
; 36(7-9): 505-524, 2022 03.
Article
in En
| MEDLINE
| ID: mdl-34498942
ABSTRACT
Aims:
Metabolic disorders may play key roles in oxidative stress and neuronal apoptosis in response to early brain injury (EBI) after subarachnoid hemorrhage (SAH). Pyruvate dehydrogenase (PDH) is related to oxidative stress in EBI, and its activity obviously decreases after SAH. We discovered that only pyruvate dehydrogenase kinase 4 (PDK4) expression was obviously increased among the four PDK isozymes after SAH in preliminary experiments. Therefore, we attempted to investigate the effects and corresponding mechanisms of PDK4 on oxidative stress after SAH.Results:
First, we confirmed that PDK4 overexpression promoted PDH phosphorylation, inhibited PDH activity, and changed cell metabolism after SAH. A small interfering RNA (siRNA) targeting PDK4, a lentiviral PDK4 overexpression vector, and dichloroacetic acid (DCA) were used to regulate the expression and activity of PDK4. The siRNA decreased PDH phosphorylation, promoted reactive oxygen species (ROS) production, activated the apoptosis signal-regulating kinase 1 (ASK1)/P38 pathway, and induced neuronal apoptosis. The lentivirus further attenuated PDH activity, oxidative stress, and neuronal apoptosis. DCA inhibited the activity of PDK4, but increased the expression of PDK4 due to a feedback mechanism. Inactivated PDK4 did not effectively suppress PDH activity, which increased ROS production, activated the ASK1/P38 pathway, and led to neuronal apoptosis. Innovation This study provides new insights into the potential antioxidant and antiapoptotic effects of the PDK4-PDH axis on EBI after SAH.Conclusions:
The early overexpression of PDK4 after SAH may attenuate neuronal apoptosis by reducing oxidative stress via the ROS/ASK1/P38 pathway. PDK4 may be a new potential therapeutic target to ameliorate EBI after SAH. Antioxid. Redox Signal. 36, 505-524.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Protein Kinases
/
Subarachnoid Hemorrhage
/
Brain Injuries
Limits:
Animals
Language:
En
Journal:
Antioxid Redox Signal
Journal subject:
METABOLISMO
Year:
2022
Document type:
Article
Affiliation country:
China