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Background Acute myocardial infarction (AMI) is one of the leading causes of cardiovascular morbidity and mortality worldwide. Pyroptosis is a form of inflammatory cell death that plays a major role in the development and progression of cardiac injury in AMI. However, the underlying mechanisms for the activation of pyroptosis during AMI are not fully elucidated. Methods and Results Here we show that RBP4 (retinol-binding protein 4), a previous identified proinflammatory adipokine, was increased both in the myocardium of left anterior descending artery ligation-induced AMI mouse model and in ischemia-hypoxia‒induced cardiomyocyte injury model. The upregulated RBP4 may contribute to the activation of cardiomyocyte pyroptosis in AMI because overexpression of RBP4 activated NLRP3 (nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3) inflammasome, promoted the precursor cleavage of Caspase-1, and subsequently induced GSDMD (gasdermin-D)-dependent pyroptosis. In contrast, knockdown of RBP4 alleviated ischemia-hypoxia‒induced activation of NLRP3 inflammasome signaling and pyroptosis in cardiomyocytes. Mechanistically, coimmunoprecipitation assay showed that RBP4 interacted directly with NLRP3 in cardiomyocyte, while genetic knockdown or pharmacological inhibition of NLRP3 attenuated RBP4-induced pyroptosis in cardiomyocytes. Finally, knockdown of RBP4 in heart decreased infarct size and protected against AMI-induced pyroptosis and cardiac dysfunction in mice. Conclusions Taken together, these findings reveal RBP4 as a novel modulator promoting cardiomyocyte pyroptosis via interaction with NLRP3 in AMI. Therefore, targeting cardiac RBP4 might represent a viable strategy for the prevention of cardiac injury in patients with AMI.

背景

急性心肌梗死（AMI）是全球心血管发病率和死亡率的主要原因之一。细胞焦亡是一种炎症细胞死亡形式，在 AMI 中心肌损伤的发生和进展中起主要作用。然而，AMI 期间细胞焦亡激活的潜在机制尚未完全阐明。

方法和结果

在这里，我们表明 RBP4（视黄醇结合蛋白 4），一种先前鉴定的促炎脂肪因子，在左前降支结扎诱导的 AMI 小鼠模型和缺血缺氧诱导的心肌细胞损伤模型的心肌中均增加。上调的 RBP4 可能导致 AMI 中心肌细胞焦亡的激活，因为 RBP4 的过表达激活了 NLRP3（核苷酸结合寡聚化结构域样受体家族 pyrin 结构域包含 3）炎症小体，促进 Caspase-1 的前体切割，随后诱导 GSDMD（gasdermin-D）依赖性细胞焦亡。相比之下，RBP4 的敲低减轻了缺血缺氧诱导的 NLRP3 炎症小体信号和心肌细胞的细胞焦亡。机制上，免疫共沉淀实验表明 RBP4 与心肌细胞中的 NLRP3 直接相互作用，而 NLRP3 的基因敲低或药理学抑制减弱了 RBP4 在心肌细胞中诱导的细胞焦亡。最后，心脏中 RBP4 的敲低减少了梗死面积，并在小鼠中保护 AMI 诱导的细胞焦亡和心脏功能障碍。