Resolvin D1 attenuates liver ischaemia/reperfusion injury through modulating thioredoxin 2-mediated mitochondrial quality control.
Br J Pharmacol
; 175(12): 2441-2453, 2018 06.
Article
em En
| MEDLINE
| ID: mdl-29569721
ABSTRACT
BACKGROUND AND PURPOSE:
Liver ischaemia and reperfusion (IR) injury is a sterile inflammatory response involving production of ROS. Mitochondrial homeostasis is maintained by mitochondrial quality control (QC). Thioredoxin (TRX) 2 is a key mitochondrial redox-sensitive protein. Resolvin D1 (RvD1), a specialized pro-resolving lipid mediator, exerts anti-inflammatory and antioxidant activities. We investigated mechanisms of RvD1 protection against IR-induced oxidative damage to the liver, focusing on TRX2-mediated mitochondrial QC. EXPERIMENTALAPPROACH:
Mice underwent partial warm IR. RvD1 was administered 1 h before ischaemia and immediately prior to reperfusion. Human liver carcinoma HepG2 cells were exposed to hypoxia/reoxygenation and transfected with TRX2 siRNA. Immunohistochemistry, Western blotting and enzyme assays were used to follow changes in mitochondrial structure and function. KEYRESULTS:
RvD1 attenuated hepatocellular damage following IR, assessed by serum aminotransferase activities and histology. RvD1 reduced mitochondrial swelling, lipid peroxidation and glutamate dehydrogenase release. Impaired activities of mitochondrial complexes I and III were restored by RvD1. RvD1 enhanced expression of the mitophagy-related protein, Parkin and inhibited accumulation of PTEN-induced putative kinase 1. RvD1 restored levels of mitochondrial biogenesis proteins including PPARγ coactivator 1α, nuclear respiratory factor 1 and mitochondrial transcription factor A and mtDNA level. RvD1 attenuated the increase in levels of the mitochondrial fission-related protein, dynamin-related protein 1. IR reduced TRX2 levels while increasing TRX2 association with TRX-interacting protein. RvD1 attenuated these changes. The regulatory effects of RvD1 on mitochondrial QC were abolished by TRX2 knockdown. CONCLUSIONS AND IMPLICATIONS We suggest that RvD1 ameliorated IR-induced hepatocellular damage by regulating TRX2-mediated mitochondrial QC.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tiorredoxinas
/
Mitocôndrias Hepáticas
/
Traumatismo por Reperfusão
/
Ácidos Docosa-Hexaenoicos
/
Hepatopatias
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Br J Pharmacol
Ano de publicação:
2018
Tipo de documento:
Article