心律失常通常与心脏成纤维细胞(CFs)的过度活跃有关。研究聚(ADP-核糖)聚合酶9(PARP9)对血管紧张素II(AngII)诱导的成纤维细胞活化的影响以及吡非尼酮(PFD)的治疗作用,为心律失常提供了宝贵的见解。本研究利用加权基因共表达网络分析(WGCNA),差异基因表达(DEG)分析,蛋白质-蛋白质相互作用(PPI),并对GSE42955数据集进行受试者工作特征(ROC)分析,以鉴定具有显著诊断价值的hub基因。ImmuCellAI工具揭示了PARP9与免疫细胞浸润之间的关联。我们的体外评估集中在PFD对肌成纤维细胞分化的影响,转化生长因子-β(TGF-β)表达,和AngII诱导的CFs增殖和迁移。此外,我们探讨了PARP9过表达对纤维化标志物和TGF-β/Smad信号通路的影响.对GSE42955数据集的分析显示PARP9是具有很高临床诊断价值的中心基因,与七种类型的免疫细胞有关。体外研究表明,PFD可显着减轻AngII诱导的CF增殖,迁移,和纤维化。它还降低了AngII诱导的PARP9表达并降低了纤维化标志物,包括TGF-β,胶原蛋白I,胶原蛋白III,和α-SMA。值得注意的是,PARP9过表达可以部分抵消PFD对CFs的抑制作用,改变纤维连接蛋白的表达,CTGF,α-SMA,胶原蛋白I,胶原蛋白III,MMP2,MMP9,TGF-β,和p-Smad2/3在TGF-β/Smad信号通路中的作用。总之,我们的研究结果表明,PFD可以有效地抵消AngII诱导的CF增殖和纤维化的不利影响,并调节TGF-β/Smad信号通路和PARP9表达。这确定了用于管理心肌纤维化的潜在治疗方法。
Cardiac arrhythmias are often linked to the overactivity of cardiac fibroblasts (CFs). Investigating the impact of poly (ADP-ribose) polymerase 9 (PARP9) on Angiotensin II (Ang II)-induced fibroblast activation and the therapeutic effects of pirfenidone (PFD) offers valuable insights into cardiac arrhythmias. This study utilized weighted gene co-expression network analysis (WGCNA), differential gene expression (DEG) analysis, protein-protein interaction (PPI), and receiver operating characteristic (ROC) analysis on the GSE42955 dataset to identify the hub gene with a significant diagnostic value. The ImmuCellAI tool revealed an association between PARP9 and immune cell infiltration. Our in vitro assessments focused on the influence of PFD on myofibroblast differentiation, transforming growth factor-beta (TGF-β) expression, and Ang II-induced proliferation and migration in CFs. Additionally, we explored the impact on fibrosis markers and the TGF-β/Smad signaling pathway in the context of PARP9 overexpression. Analysis of the GSE42955 dataset revealed PARP9 as a central gene with high clinical diagnostic value, linked to seven types of immune cells. The in vitro studies demonstrated that PFD significantly mitigates Ang II-induced CF proliferation, migration, and fibrosis. It also reduces Ang II-induced PARP9 expression and decreases fibrosis markers, including TGF-β, collagen I, collagen III, and α-SMA. Notably, PARP9 overexpression can partially counteract PFD\'s inhibitory effects on CFs and modify the expression of fibronectin, CTGF, α-SMA, collagen I, collagen III, MMP2, MMP9, TGF-β, and p-Smad2/3 in the TGF-β/Smad signaling pathway. In summary, our findings suggest that PFD effectively counteracts the adverse effects of Ang II-induced CF proliferation and fibrosis, and modulates the TGF-β/Smad signaling pathway and PARP9 expression. This identifies a potential therapeutic approach for managing myocardial fibrosis.