RESUMO
Coronavirus disease 2019 (COVID-19) affected people worldwide, and fever is one of the major symptoms of this disease. Although Acetaminophen (APAP) is a common fever-reducing medication, it can also mediate liver injury. However, the role of PGC-1α in regulating mitochondrial quality control by lactate dehydrogenase B (LDHB), a vital enzyme catalyzing the conversion of lactate to pyruvate, in APAP-induced hepatotoxicity, is unclear. Here, gene expression omnibus data of patients with APAP-induced liver injury were used to explore gene expression profiles. AML12 cells and C57/BL6 mice were used to establish models of APAP-induced acute liver injury. SIRT1 and PGC-1α were overexpressed in vitro via lentiviral transfection to establish stable cell lines. The results showed that APAP treatment decreased SIRT1/PGC-1α/LDHB expression and increased protein lactylation, mitochondrial lactate levels, and pathological damage in liver mitochondria. PGC-1α upregulation or activation ameliorated APAP-induced damage in the cells and liver. Furthermore, PGC-1α overexpression increased LDHB synthesis, reduced lactylation, and induced a switch from lactate to pyruvate production. These results suggest that PGC-1α and LDHB play a role in APAP-induced liver injury by regulating mitochondrial quality control and lactate metabolic reprogramming. Therefore, the PGC-1α/LDHB axis is a potential therapeutic target for APAP-induced liver injury.
Assuntos
Acetaminofen , Doença Hepática Induzida por Substâncias e Drogas , L-Lactato Desidrogenase , Camundongos Endogâmicos C57BL , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Animais , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Camundongos , Humanos , Masculino , L-Lactato Desidrogenase/metabolismo , Ácido Láctico/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Linhagem Celular , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Hepáticas/efeitos dos fármacos , Sirtuína 1/metabolismo , Sirtuína 1/genética , IsoenzimasRESUMO
BACKGROUND: This study evaluates the relationship between global longitudinal strain (GLS) and late major adverse cardiovascular events (MACEs) in patients after acute myocardial infarction (AMI). METHODS: Data of newly diagnosed AMI patients between March 2010 and July 2014 were retrospectively evaluated. The patients underwent serial echocardiography at admission and at third and sixth months post-admission. We calculated GLS by averaging the strain from all myocardial segments using speckle-tracking echocardiography (STE). We used multivariate Cox regression analysis and receiver operating characteristic (ROC) curve analyses to assess the relationship between GLS at admission and late MACEs. RESULTS: Eighty-nine newly diagnosed AMI patients were enrolled. The average age at diagnosis was 61 ± 12.5 years, and approximately 89.9% of the patients were men. The average level of GLS was -17.5 ± 3.9%. The overall prevalence of MACEs was 23.6% (21/89), compared with 44 % (11/25) in the group with GLS≥-15 % and 17.9% (5/28) in the group with GLS<-20%. GLS was positively linked with MACEs in the fully adjusted Cox proportional hazard model (hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.04-1.37; P=0.014) after adjusting potential confounders. The ROC curve analysis for one year MACEs between GLS at admission, with the most significant area under the curve(AUC) 78.1% (95% CI, 63.8% - 92.6%). CONCLUSIONS: Myocardial dysfunction, characterized by impaired GLS, is often observed in AMI patients, and a decrease in GLS levels at admission were associated with an increased risk of long-term MACEs in post-myocardial infarction patients.