Aims While the pivotal role of inflammation in pathological cardiac hypertrophy and remodelling is widely acknowledged, the mechanisms triggering inflammation initiation remain largely obscure. This study aims to elucidate the role and mechanism of serpin family B member 1 (SerpinB1) in pro-inflammatory cardiomyocyte pyroptosis, heart inflammation, and cardiac remodelling. Methods and results C57BL/6J wild-type, inducible cardiac-specific SerpinB1 overexpression or knockout mice underwent transverse aortic constriction (TAC) surgery. Cardiac hypertrophy and remodelling were assessed through echocardiography and histology. Cardiomyocyte pyroptosis and heart inflammation were monitored. Adeno-associated virus 9 -mediated gene manipulations and molecular assays were employed to explore the mechanisms through which SerpinB1 regulates cardiomyocyte pyroptosis and heart inflammation. Finally, recombinant mouse SerpinB1 protein (rSerpinB1) was administrated both in vivo through osmotic minipump delivery and in vitro to investigate the therapeutic potential of SerpinB1 in cardiac remodelling. Myocardial SerpinB1 overexpression was up-regulated shortly upon TAC or phenylephrine challenge, with no further elevation during prolonged hypertrophic stimuli. It is important to note that cardiac-specific overexpression of SerpinB1 markedly attenuated TAC-induced cardiac remodelling, while deletion of SerpinB1 exacerbated it. At the mechanistic level, SerpinB1 gain-of-function inhibited cardiomyocyte pyroptosis and inflammation in hypertrophic hearts; the protective effect was nullified by overexpression of either cleaved N-terminal gasdermin D or cleaved caspase-1. Co-immunoprecipitation and confocal assays confirmed that SerpinB1 directly interacts with caspase-1 in cardiomyocytes. Remarkably, rSerpinB1 replicated the cardioprotective effect against cardiac hypertrophy and remodelling. Conclusion SerpinB1 safeguards against pathological cardiac hypertrophy and remodelling by impeding cardiomyocyte pyroptosis to suppress inflammation initiation, achieved through interaction with caspase-1 to inhibit its activation. Targeting SerpinB1 could represent a novel therapeutic strategy for treating pathological cardiac hypertrophy and remodelling.

中文翻译：

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SerpinB1 靶向通过抑制心肌细胞焦亡和炎症发生来防止病理性心脏肥大和重塑


目的 虽然炎症在病理性心脏肥大和重塑中的关键作用已得到广泛认可，但触发炎症发生的机制在很大程度上仍然不清楚。本研究旨在阐明丝氨酸蛋白酶抑制剂家族 B 成员 1 （SerpinB1） 在促炎心肌细胞焦亡、心脏炎症和心脏重塑中的作用和机制。方法和结果 C57BL/6J 野生型、诱导型心脏特异性 SerpinB1 过表达或敲除小鼠行横主动脉缩窄 （TAC） 手术。通过超声心动图和组织学评估心脏肥大和重塑。监测心肌细胞焦亡和心脏炎症。采用腺相关病毒 9 介导的基因操作和分子测定来探索 SerpinB1 调节心肌细胞焦亡和心脏炎症的机制。最后，通过渗透微型泵输送在体内和体外施用重组小鼠 SerpinB1 蛋白 （rSerpinB1），以研究 SerpinB1 在心脏重塑中的治疗潜力。心肌 SerpinB1 过表达在 TAC 或去氧肾上腺素攻击后不久上调，在长时间肥大刺激期间没有进一步升高。值得注意的是，SerpinB1 的心脏特异性过表达显着减弱了 TAC 诱导的心脏重塑，而 SerpinB1 的缺失加剧了它。在机制水平上，SerpinB1 功能获得抑制肥厚性心脏心肌细胞焦亡和炎症;过表达裂解的 N 末端 gasdermin D 或裂解的 caspase-1 会抵消保护作用。免疫共沉淀和共聚焦测定证实 SerpinB1 直接与心肌细胞中的 caspase-1 相互作用。 值得注意的是，rSerpinB1 复制了对心脏肥大和重塑的心脏保护作用。结论 SerpinB1 通过与 caspase-1 相互作用抑制其激活，通过阻碍心肌细胞焦亡来抑制炎症的发生，从而防止病理性心脏肥大和重塑。靶向 SerpinB1 可能代表一种治疗病理性心脏肥大和重塑的新型治疗策略。