PDF(Pubmed)
Abstract：
Isoproterenol (ISO) administration is a well-established model for inducing myocardial injury, replicating key features of human myocardial infarction (MI). The ensuing inflammatory response plays a pivotal role in the progression of adverse cardiac remodeling, characterized by myocardial dysfunction, fibrosis, and hypertrophy. The Mst1/Hippo signaling pathway, a critical regulator of cellular processes, has emerged as a potential therapeutic target in cardiovascular diseases. This study investigates the role of Mst1 in ISO-induced myocardial injury and explores its underlying mechanisms. Our findings demonstrate that Mst1 ablation in cardiomyocytes attenuates ISO-induced cardiac dysfunction, preserving cardiomyocyte viability and function. Mechanistically, Mst1 deletion inhibits cardiomyocyte apoptosis, oxidative stress, and calcium overload, key contributors to myocardial injury. Furthermore, Mst1 ablation mitigates endoplasmic reticulum (ER) stress and mitochondrial fission, both of which are implicated in ISO-mediated cardiac damage. Additionally, Mst1 plays a crucial role in modulating the inflammatory response following ISO treatment, as its deletion suppresses pro-inflammatory cytokine expression and neutrophil infiltration. To further investigate the molecular mechanisms underlying ISO-induced myocardial injury, we conducted a bioinformatics analysis using the GSE207581 dataset. GO and KEGG pathway enrichment analyses revealed significant enrichment of genes associated with DNA damage response, DNA repair, protein ubiquitination, chromatin organization, autophagy, cell cycle, mTOR signaling, FoxO signaling, ubiquitin-mediated proteolysis, and nucleocytoplasmic transport. These findings underscore the significance of Mst1 in ISO-induced myocardial injury and highlight its potential as a therapeutic target for mitigating adverse cardiac remodeling. Further investigation into the intricate mechanisms of Mst1 signaling may pave the way for novel therapeutic interventions for myocardial infarction and heart failure.
摘要：
异丙肾上腺素（ISO）给药是一个公认的诱导心肌损伤的模型，复制人心肌梗死（MI）的关键特征。随之而来的炎症反应在不良心脏重塑的进展中起着关键作用，以心肌功能障碍为特征，纤维化，和肥大。Mst1/Hippo信号通路,细胞过程的关键调节器，已经成为心血管疾病的潜在治疗靶点。本研究探讨了Mst1在ISO诱导的心肌损伤中的作用，并探讨了其潜在的机制。我们的研究结果表明，Mst1在心肌细胞中的消融减弱ISO诱导的心功能不全，保持心肌细胞的活力和功能。机械上,Mst1缺失抑制心肌细胞凋亡,氧化应激，钙超载，心肌损伤的主要原因。此外，Mst1消融减轻内质网（ER）应激和线粒体裂变，两者都与ISO介导的心脏损伤有关。此外,Mst1在调节ISO治疗后的炎症反应中起着至关重要的作用，因为它的缺失抑制了促炎细胞因子的表达和中性粒细胞的浸润。进一步探讨ISO诱导心肌损伤的分子机制,我们使用GSE207581数据集进行了生物信息学分析.GO和KEGG途径富集分析显示与DNA损伤反应相关的基因显著富集，DNA修复,蛋白质泛素化，染色质组织，自噬,细胞周期,mTOR信令,FoxO信号,泛素介导的蛋白水解，和核质运输。这些发现强调了Mst1在ISO诱导的心肌损伤中的重要性，并强调了其作为减轻不良心脏重塑的治疗靶标的潜力。对Mst1信号传导的复杂机制的进一步研究可能为心肌梗死和心力衰竭的新型治疗干预铺平道路。
