PANoptosis是一种新发现的细胞死亡类型,其特征是焦亡,细胞凋亡和/或坏死,并已参与炎症反应。Piezo1是一种机械敏感性离子通道,在生理发育和各种疾病中起重要作用。然而,心肌细胞在心肌缺血/再灌注(I/R)损伤过程中是否发生PANoptosis,以及Piezo1在这一过程中的作用仍未被研究.在这项研究中,我们的结果表明,PANopsome的主要成分的表达水平,包括caspase-8,caspase-3,NLRP3,caspase-1,GSDMD,RIPK1,RIPK3和MLKL,随着时间的推移,在I/R心脏组织中显著上调,提示I/R心脏发生PANoptesis。因此,在I/R损伤的心脏和缺氧/复氧(H/R)处理的心肌细胞中,Piezo1表达显着上调。相比之下,在小鼠中通过抑制剂GsMTx4对Piezo1的药理抑制作用显着减弱了I/R介导的心脏收缩功能下降并增加了梗死面积,凋亡,氧化应激和炎症伴随着抑制I/R心脏中PANoptosis相关介质。始终如一,在体外H/R处理的心肌细胞中,通过GsMTx4和Piezo1激活剂Yoda1进一步验证了Piezo1对钙内流和PANoptosis的影响。此外,在体外H/R诱导的PANoptosis需要caspase-8而不是钙内流。机械上,Piezo1与PANoposome复合物的关键初始激活剂caspase-8相互作用,随后激活心肌细胞全景下垂,导致心脏功能障碍.总之,这些数据提示Piezo1是一种新的心脏机械传感器,可能通过caspase-8介导的心肌细胞PANoptocol激活来促进心脏I/R损伤,并强调Piezo1可能成为治疗缺血性心脏病的新靶点.
PANoptosis is a newly discovered type of cell death characterized by pyroptosis, apoptosis and/or necroptosis and has been implicated in the inflammatory response. Piezo1 is a mechanosensitive ion channel that plays important roles in physiological development and various diseases. However, whether cardiomyocytes undergo PANoptosis during myocardial ischaemia/reperfusion (I/R) injury and the role of Piezo1 in this process remain largely unexplored. In this study, our results revealed that the expression levels of the main components of the PANoptosome, including caspase-8, caspase-3, NLRP3, caspase-1, GSDMD, RIPK1, RIPK3 and MLKL, were significantly upregulated in I/R heart tissues over time, indicating the occurrence of PANoptosis in I/R hearts. Accordingly, Piezo1 expression was significantly upregulated in I/R-injured hearts and hypoxia/reoxygenation (H/R)-treated cardiomyocytes. In contrast, pharmacological inhibition of Piezo1 by the inhibitor GsMTx4 in mice markedly attenuated the I/R-mediated decline in cardiac contractile function and increases in infarct size, apoptosis, oxidative stress and inflammation accompanied by the inhibition of PANoptosis-related mediators in I/R hearts. Consistently, the effects of Piezo1 on calcium influx and PANoptosis were further verified by GsMTx4 and Piezo1 activator Yoda1 in H/R-treated cardiomyocytes in vitro. Moreover, caspase-8 rather than calcium influx was required for H/R-induced PANoptosis in vitro. Mechanistically, Piezo1 interacts with caspase-8, a key initial activator of the PANoptosome complex, which subsequently activates cardiomyocyte PANoptosis, leading to cardiac dysfunction. In summary, these data suggest that Piezo1 is a new cardiac mechanosensor that promotes cardiac I/R injury possibly through the caspase-8-mediated activation of cardiomyocyte PANoptosis and highlight that Piezo1 may represent a new target for treating ischaemic heart disease.