Extracellular RIPK3 Acts as a Damage-Associated Molecular Pattern to Exaggerate Cardiac Ischemia/Reperfusion Injury

作者：Wenjia Zhang, Junxia Zhang, Zeyuan Wang, Ting Li, C F Liu, Xuya Kang, Xiaomeng Cui, Jingli Yang, Huilin Qu, Jiaxin Duanmu, Ying Peng, Kai Wang, Jin Li, Peng Xie, Wen Zheng, Haibao Shang, Yahan Liu, Zhuang Tian, Zhenyu Liu, Ye Jin, Yingjia Li, Nan Li, Xiaozhen Zhuo, Yue Wu, Xiaolu Shi, Rui Ma, Yueshen Sun, Kai Zhang, Xiangming Fang, Xiaomin Hu, Erdan Dong, Shuyang Zhang, Yan Zhang · 发表于：Circulation · 年份：2024 · DOI：10.1161/circulationaha.123.068595 · 被引用次数：39 · 研究领域：Cell death mechanisms and regulation、Immune Response and Inflammation、Phagocytosis and Immune Regulation

BACKGROUND: Cardiac ischemia/reperfusion (I/R) injury has emerged as an important therapeutic target for ischemic heart disease. Currently, there is no effective therapy for reducing cardiac I/R injury. Damage-associated molecular patterns are endogenous molecules released after cellular damage to exaggerate tissue inflammation and injury. RIPK3 (receptor-interacting protein kinase 3), a well-established intracellular mediator of cell necroptosis and inflammation, serves as a circulating biomarker of multiple diseases. However, whether extracellular RIPK3 also exerts biological functions in cardiac I/R injury remains totally unknown. METHODS: Patients with acute myocardial infarction receiving percutaneous coronary intervention (PCI) were recruited independently in the discovery cohort (103 patients) and validation cohort (334 patients), and major adverse cardiovascular events were recorded. Plasma samples were collected before and after PCI (6 and 24 h) for RIPK3 concentration measurement. Cultured neonatal rat ventricular myocytes, macrophages and endothelial cells, and in vivo mouse models with myocardial injury induced by I/R (or hypoxia/reoxygenation) were used to investigate the role and mechanisms of extracellular RIPK3. Another cohort including patients with acute myocardial infarction receiving PCI and healthy volunteers was recruited to further explore the mechanisms of extracellular RIPK3. RESULTS: In the discovery cohort, elevated plasma RIPK3 levels after PCI are...