南方医科大学学报

南方医科大学学报 ›› 2021, Vol. 41 ›› Issue (10): 1534-1539.doi: 10.12122/j.issn.1673-4254.2021.10.12

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RIP1/RIP3-MLKL信号通路与慢性心力衰竭的发生、发展及预后相关

陈永锋，李小荣，赖薇薇，朱飞宇，谭 鑫，鲜 维，康品方，王洪巨   

  1. 蚌埠医学院第一附属医院心血管科，心脑血管病基础与临床重点实验室，医学影像学院2017级1班，安徽 蚌埠 233000
  • 出版日期:2021-10-20 发布日期:2021-11-11

RIP1/RIP3-MLKL signaling pathway correlates with occurrence, progression and prognosis of chronic heart failure

CHEN Yonfeng, LI Xiaorong, LAI Weiwei, ZHU Feiyu, TAN Xin, XIAN Wei, KANG Pinfang, WANG Hongju   

  1. Department of Cardiology, First Affiliated Hospital, Cardiovascular and Cerebrovascular Disease Research Center, Class 1, Grade 2017, School of Medical Imaging, Bengbu Medical College, Bengbu 233000, China
  • Online:2021-10-20 Published:2021-11-11

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摘要： 目的 通过检测正常人与慢性心力衰竭（HF）患者血浆中受体相互作用的蛋白激酶RIP1、RIP3和混合谱系激酶结构域样蛋白MLKL的表达水平，探讨程序性坏死信号通路RIP1/RIP3-MLKL在HF过程中的表达规律及临床意义。方法 入选2020年2 月~2020年10月在我院接受治疗的慢性HF患者（NYHA Ⅱ~Ⅳ级）。正常对照组（n=21），Ⅱ级（n=20），Ⅲ级（n=33），Ⅳ级（n=43）。采集所有患者的空腹静脉血，ELISA法和Western blotting分别检测RIP1/RIP3-MLKL表达水平和通路蛋白表达情况，同时对心功能Ⅳ级患者进行为期5个月的临床随访，评估临床预后指标。结果 与正常对照组相比，心功能Ⅱ、Ⅲ、Ⅳ级组RIP1、RIP3、MLKL表达量均增加（P<0.01）；与II级组相比，心功能Ⅲ、Ⅳ级组RIP1、RIP3、MLKL表达量均增加（P<0.01）；与Ⅲ级组相比，心功能Ⅳ级组RIP1、MLKL表达量增加（P<0.05）。WB检测RIP1/RIP3-MLKL通路中各蛋白表达量，均存在上调趋势。经pearson相关性分析，HF患者RIP1/RIP3-MLKL表达量与Scr、AST、LVEDD、NT-ProBNP呈正相关（r=0.375、0.231、0.238、0.339、 0.299、0.373、0.228、0.256、0.253、0.184、0.189、0.187，P<0.05），与LVEF呈负相关（r=-0.268、-0.234、-0.322，P<0.05）。此外对临床随访结果运用独立样本t检验分析，发现在心功能Ⅳ级患者中RIP1/RIP3-MLKL表达量更高组临床预后指标更差。结论 RIP1-RIP3-MLKL信号通路在HF患者中表达明显增加，与HF严重程度呈正相关；慢性HF的发生、发展及预后可能与RIP1/RIP3-MLKL信号通路的激活与表达有关。

关键词: 慢性心力衰竭；RIP1；RIP3；MLKL；程序性坏死

Abstract: Objective To detect plasma levels of receptor-interacting protein kinase 1 (RIP1), RIP3 and mixed lineage kinase domain-like protein (MLKL) in patients with chronic heart failure and explore the expression pattern of programmed necrosis signaling pathway RIP1/RIP3-MLKL in the progression of heart failure. Methods The patients with chronic heart failure (NYHA class II-IV) admitted in our hospital between February, 2020 and March, 2021 were prospectively enrolled in this study, with 21 healthy volunteers as the control group. The enrolled patients included 20 with grade II, 33 with grade III, and 43 with grade IV cardiac function. Fasting venous blood was collected from all the participants for detecting plasma levels of RIP1, RIP3, and MLKL and protein expressions of RIP1/RIP3-MLKL pathway using enzyme-linked immunosorbent assay (ELISA) and Western blotting. The patients with grade IV cardiac function were followed up for 5 months to evaluate the clinical prognostic indicators. Results Compared with the healthy volunteers, the patients with grade II, III and IV cardiac function had significantly increased plasma levels of RIP1, RIP3, and MLKL (P<0.01), and their levels were significantly higher in grade III/IV patients than in those with grade II cardiac function (P<0.01); the plasma levels of RIP1 and MLKL were significantly higher in grade IV patients than in grade III patients (P<0.05). The results of Western blotting also showed increased expressions of the proteins in the RIP1/RIP3-MLKL pathway in patients with heart failure. Pearson correlation analysis suggested that in patients with heart failure, the expression levels of RIP1, RIP3, and MLKL were positively correlated with SCR, AST, LVEDD and NT-proBNP (P<0.05). Follow-up study of the patients with grade IV cardiac function showed that higher expression levels of RIP1/RIP3-MLKL were associated with a poorer prognosis of the patients. Conclusion The expressions of RIP1, RIP3 and MLKL are significantly upregulated in patients with heart failure in positive correlation with the severity of the disease condition, and the activation of the RIP1/RIP3-MLKL signaling pathway may contribute to the occurrence, development and prognosis of chronic heart failure.

Key words: chronic heart failure; receptor-interacting protein kinase 1; receptor-interacting protein kinase 3; mixed lineage kinase domain-like protein; programmed necrosis