20-HETE synthesis inhibition attenuates traumatic brain injury-induced mitochondrial dysfunction and neuronal apoptosis via the SIRT1/PGC-1α pathway: A translational study.

Abstract

OBJECTIVES:

20-hydroxyeicosatetraenoic acid (20-HETE) is a metabolite of arachidonic acid catalysed by cytochrome P450 enzymes and plays an important role in cell death and proliferation. We hypothesized that 20-HETE synthesis inhibition may have protective effects in traumatic brain injury (TBI) and investigated possible underlying molecular mechanisms.

MATERIALS AND METHODS:

Neurologic deficits, and lesion volume, reactive oxygen species (ROS) levels and cell death as assessed using immunofluorescence staining, transmission electron microscopy and Western blotting were used to determine post-TBI effects of HET0016, an inhibitor of 20-HETE synthesis, and their underlying mechanisms.

RESULTS:

The level of 20-HETE was found to be increased significantly after TBI in mice. 20-HETE synthesis inhibition reduced neuronal apoptosis, ROS production and damage to mitochondrial structures after TBI. Mechanistically, HET0016 decreased the Drp1 level and increased the expression of Mfn1 and Mfn2 after TBI, indicating a reversal of the abnormal post-TBI mitochondrial dynamics. HET0016 also promoted the restoration of SIRT1 and PGC-1α in vivo, and a SIRT1 activator (SRT1720) reversed the downregulation of SIRT1 and PGC-1α and the abnormal mitochondrial dynamics induced by 20-HETE in vitro. Furthermore, plasma 20-HETE levels were found to be higher in TBI patients with unfavourable neurological outcomes and were correlated with the GOS score.

CONCLUSIONS:

The inhibition of 20-HETE synthesis represents a novel strategy to mitigate TBI-induced mitochondrial dysfunction and neuronal apoptosis by regulating the SIRT1/PGC-1α pathway.

• Authors: Wenxing Cui, Xun Wu, Yingwu Shi, Wei Guo, Jianing Luo, Haixiao Liu, Longlong Zheng, Yong Du, Ping Wang, Qiang Wang, Dayun Feng, Shunnan Ge, Yan Qu
• Journal: Cell proliferation (Cell Prolif) Vol. 54 Issue 2 Pg. e12964 (Feb 2021) ISSN: 1365-2184 [Electronic] England
• PMID: 33314534 (Publication Type: Journal Article)
• Copyright: © 2020 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd.

Chemical References

• Amidines
• HET0016
• Hydroxyeicosatetraenoic Acids
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Ppargc1a protein, mouse
• Reactive Oxygen Species
• 20-hydroxy-5,8,11,14-eicosatetraenoic acid
• Sirt1 protein, mouse
• Sirtuin 1
• DNM1L protein, human
• Dynamins

Topics

• Amidines (pharmacology)
• Animals
• Apoptosis (drug effects)
• Brain Injuries, Traumatic (pathology, veterinary)
• Dynamins (metabolism)
• Female
• Humans
• Hydroxyeicosatetraenoic Acids (blood, metabolism, pharmacology)
• Logistic Models
• Male
• Mice
• Mice, Inbred C57BL
• Middle Aged
• Mitochondria (metabolism, ultrastructure)
• Mitochondrial Dynamics (drug effects)
• Neurons (cytology, metabolism, ultrastructure)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Sirtuin 1 (chemistry, metabolism)