RESUMO
Doxorubicin (DOX) is restricted due to its severe cardiotoxicity. There is still a lack of viable and effective drugs to prevent or treat DOX-induced cardiotoxicity(DIC). Vericiguat is widely used to treat heart failure with reduced ejection fraction. However, it is not clear whether vericiguat can improve DIC. In the present study, we constructed a DIC model using mice and neonatal rat cardiomyocytes and found that vericiguat ameliorated DOX-induced cardiac insufficiency in mice, restored DOX-induced mitochondrial dysfunction in neonatal rat cardiomyocytes, and inhibited the expression of inflammatory factors. Further studies showed that vericiguat improved mitochondrial dysfunction and reduced mtDNA leakage into the cytoplasm by up-regulating PRKG1, which activated PINK1 and then inhibited the STING/IRF3 pathway to alleviate DIC. These findings demonstrate for the first time that vericiguat has therapeutic potential for the treatment of DIC.
Assuntos
Cardiotoxicidade , Doxorrubicina , Proteínas de Membrana , Miócitos Cardíacos , Proteínas Quinases , Animais , Doxorrubicina/efeitos adversos , Doxorrubicina/toxicidade , Cardiotoxicidade/prevenção & controle , Cardiotoxicidade/etiologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Camundongos , Proteínas Quinases/metabolismo , Ratos , Masculino , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Ratos Sprague-DawleyRESUMO
Post-myocardial infarction heart failure (HF) is a major public health concern. Previous studies have reported the critical role of immune response in HF pathogenesis. However, limited studies have reported predictive immune-associated biomarkers for HF. So we attempted to identify potential immune-related indicators for HF early diagnosis and therapy guidance. This study identified two potential immune-related hub genes (IRHGs), namely CXCR5 and FOS, using bioinformatic approaches. The expression levels of CXCR5 and FOS and their ability to predict long-term HF were analyzed. Functional enrichment analysis revealed that the hub genes were enriched in immune system processes, including the interleukin-17 and nuclear factor-kappa B signaling pathways, which are involved in the pathogenesis of HF. Quantitative real-time polymerase chain reaction revealed that the Fos mRNA levels, but not the Cxcr5 mRNA levels, were downregulated in the mice of the HF group. This study successfully identified two IRHGs that were significantly and differentially expressed in the HF group and could predict long-term HF, providing novel insights for future studies on HF and developing novel therapeutic targets for HF.