Retinol-Binding Protein 4 Promotes Cardiac Injury After Myocardial Infarction Via Inducing Cardiomyocyte Pyroptosis Through an Interaction With NLRP3.
Retinol-Binding Protein 4 Promotes Cardiac Injury After Myocardial Infarction Via Inducing Cardiomyocyte Pyroptosis Through an Interaction With NLRP3.
复制标题
视黄醇结合蛋白 4 通过与 NLRP3 相互作用诱导心肌细胞焦亡，促进心肌梗塞后的心脏损伤。
DOI：
10.1161/jaha.121.022011
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发表时间：
2021-11-16
影响因子：
5.4
通讯作者：
Gao W
中科院分区：
文献类型：
--
作者：
Zhang KZ;Shen XY;Wang M;Wang L;Sun HX;Li XZ;Huang JJ;Li XQ;Wu C;Zhao C;Liu JL;Lu X;Gao W
急性心肌梗死（AMI）是全世界心血管疾病发病和死亡的主要原因之一。细胞焦亡是炎症细胞死亡的一种形式，在 AMI 心脏损伤的发生和进展中发挥着重要作用。然而，AMI 期间细胞焦亡激活的潜在机制尚未完全阐明。在这里，我们发现 RBP4（视黄醇结合蛋白 4）是一种先前发现的促炎脂肪因子，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中的心肌均增加。 RBP4的上调可能有助于AMI中心肌细胞焦亡的激活，因为RBP4的过度表达激活了NLRP3（核苷酸结合寡聚化结构域样受体家族pyrin结构域3）炎症小体，促进了Caspase-1的前体裂解，随后诱导GSDMD（gasdermin-D）依赖性焦亡。相反，RBP4 的敲低减轻了缺血缺氧诱导的 NLRP3 炎性体信号传导激活和心肌细胞焦亡。从机制上讲，免疫共沉淀测定表明，RBP4 直接与心肌细胞中的 NLRP3 相互作用，而 NLRP3 的基因敲除或药物抑制可减轻 RBP4 诱导的心肌细胞焦亡。最后，敲低心脏中的 RBP4 可减少梗死面积，并防止小鼠出现 AMI 诱导的细胞焦亡和心功能障碍。综上所述，这些发现表明 RBP4 作为一种新型调节剂，通过与 AMI 中的 NLRP3 相互作用促进心肌细胞焦亡。因此，针对心脏 RBP4 可能是预防 AMI 患者心脏损伤的可行策略。
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. 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. 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.