RESUMEN
The specific pathophysiological pathways through which diabetes exacerbates myocardial ischemia/reperfusion (I/R) injury remain unclear; however, dysregulation of immune and inflammatory cells, potentially driven by abnormalities in their number and function due to diabetes, may play a significant role. In the present investigation, we simulated myocardial I/R injury by inducing ischemia through ligation of the left anterior descending coronary artery in mice for 40 min, followed by reperfusion for 24 h. Previous studies have indicated that protein kinase Cß (PKCß) is upregulated under hyperglycemic conditions and is implicated in the development of various diabetic complications. The Y4 RNA fragment is identified as the predominant small RNA component present in the extracellular vesicles of cardio sphere-derived cells (CDCs), exhibiting notable anti-inflammatory properties in the contexts of myocardial infarction and cardiac hypertrophy. Our investigation revealed that the administration of Y4 RNA into the ventricular cavity of db/db mice following myocardial I/R injury markedly enhanced cardiac function. Furthermore, Y4 RNA was observed to facilitate M2 macrophage polarization and interleukin-10 secretion through the suppression of PKCß activation. The mechanism by which Y4 RNA affects PKCß by regulating macrophage activation within the inflammatory environment involves the inhibition of ERK1/2 phosphorylation In our study, the role of PKCß in regulating macrophage polarization during myocardial I/R injury was investigated through the use of PKCß knockout mice. Our findings indicate that PKCß plays a crucial role in modulating the inflammatory response associated with macrophage activation in db/db mice experiencing myocardial I/R, with a notable exacerbation of this response observed upon significant upregulation of PKCß expression. In vitro studies further elucidated the protective mechanism by which Y4 RNA modulates the PKCß/ERK1/2 signaling pathway to induce M2 macrophage activation. Overall, our findings suggest that Y4 RNA plays an anti-inflammatory role in diabetic I/R injury, suggesting a novel therapeutic approach for managing myocardial I/R injury in diabetic individuals.
Asunto(s)
Modelos Animales de Enfermedad , Macrófagos , Ratones Endogámicos C57BL , Daño por Reperfusión Miocárdica , Proteína Quinasa C beta , Transducción de Señal , Animales , Proteína Quinasa C beta/metabolismo , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/enzimología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/genética , Macrófagos/metabolismo , Macrófagos/enzimología , Masculino , Interleucina-10/metabolismo , Interleucina-10/genética , Ratones , Cardiomiopatías Diabéticas/enzimología , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/etiología , Cardiomiopatías Diabéticas/genética , Cardiomiopatías Diabéticas/fisiopatología , Células Cultivadas , Fenotipo , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/patología , Miocitos Cardíacos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Activación de Macrófagos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Función Ventricular Izquierda , FosforilaciónRESUMEN
Chronic necroinflammation in liver induces lipid peroxidation and oxidative stress, which contributes to hepatocellular carcinoma (HCC) development. Gamma-hydroxy-1, N2-propanodeoxyguanosine (γ-OHPdG), a promutagenic DNA adduct, is derived from lipid peroxidation. Little is known about the clinical roles of γ-OHPdG in relationship to HCC progression. Here, we showed that γ-OHPdG levels were highly expressed in the cancerous HCC tissues (P = 0.020, compared to those in noncancerous parts). Postoperative outcome analysis revealed that higher γ-OHPdG expression in the paraneoplastic noncancerous tissues was independently associated with shorter distant metastasis-free survival (P = 0.020). In subgroup analysis, higher γ-OHPdG expression in the noncancerous tissues in hepatitis B related HCC subgroup was associated with shorter overall survival (P = 0.016) and distant metastasis-free survival (P = 0.006). However, in patient subgroups including non-cirrhosis, bilirubin < 1.2 mg/dL, alanine transaminase < 41 U/L, or aspartate transaminase < 31 U/L, higher γ-OHPdG expression in the cancerous tissues was associated with longer overall survival (P < 0.03 for all). In vitro experiments showed that cell viability was suppressed upon hydrogen peroxide treatment in liver cancer cell lines. In conclusion, lipid peroxidation derived marker, γ-OHPdG, in the paraneoplastic noncancerous and cancerous liver tissues predicted postoperative outcomes in HCC patients.