Uric acid aggravates myocardial ischemia-reperfusion injury via ROS/NLRP3 pyroptosis pathway
Uric acid aggravates myocardial ischemia-reperfusion injury via ROS/NLRP3 pyroptosis pathway
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DOI：
10.1016/j.biopha.2020.110990
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发表时间：
2021-01-01
影响因子：
7.5
通讯作者：
Sheng, JianLong
中科院分区：
文献类型：
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作者：
Shen, ShiChun;He, Fei;Sheng, JianLong
背景资料：NOD样受体pyrin domain containing protein 3（NLRP 3）炎性小体激活介导的细胞凋亡途径与心肌缺血再灌注（MI/R）损伤有关。方法：采用结扎小鼠左冠状动脉建立MI/R模型，腹腔注射氧酸钾（PO）建立小鼠高尿酸血症模型。检测心肌梗死面积、末端脱氧核苷酸转移酶缺口末端标记法（TUNEL）、血清乳酸脱氢酶（LDH）、肌酸激酶同工酶（CK-MB）、尿酸（UA）水平及心肌组织中凋亡相关蛋白和caspase-3的表达水平。另外，体外培养原代小鼠心肌细胞以建立缺氧/复氧（H/R）模型。然后，我们比较了心肌细胞的活力，TUNEL免疫荧光，以及心肌细胞中LDH，活性氧（ROS），热解相关蛋白和caspase-3的水平。在体内，MI/R组的MI面积、CK-MB和LDH水平、细胞死亡率、细胞凋亡相关蛋白和caspase-3的表达均显著高于Sham组，高尿酸水平使这些变化恶化。体外实验结果显示，与HR组相比，H/R + UA组心肌细胞活力明显下降，ROS、LDH、pyroptosis相关蛋白、caspase-3水平及心肌细胞死亡率明显升高。NLRP 3炎性体抑制剂和ROS清除剂的管理逆转了这些effects.Conclusion：UA通过促进ROS的产生，而炎性体抑制剂和ROS清除剂部分逆转了MI/R诱导的NLRP 3炎性级联反应的激活和焦亡。
Background: The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome activation-mediated pyroptosis pathway has been linked to myocardial ischemia-reperfusion (MI/R) injury. This study explored whether uric acid (UA) aggravates MI/R injury through NLRP3 inflammasome-mediated pyroptosis.Methods: In vivo, a mouse MI/R model was established by ligating the left coronary artery, and a mouse hyperuricemia model was created by intraperitoneal injection of potassium oxonate (PO). Then, the myocardial infarction (MI) size; terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) immunofluorescence; and serum levels of lactate dehydrogenase (LDH), creatine kinase isoenzyme (CK-MB), and UA, as well as the expression level of pyroptosis-related protein and caspase-3 in heart tissues, were measured. Separately, primary mouse cardiomyocytes were cultured in vitro to create a hypoxia/reoxygenation (H/R) model. We then compared cardiomyocytes viability, TUNEL immunofluorescence, and the levels of LDH, reactive oxygen species (ROS), and pyroptosis-related protein and caspase-3 in cardiomyocytes.Results: In vivo, the MI area, levels of CK-MB and LDH, rate of cell death, and pyroptosis-related protein and the expression of caspase-3 were significantly higher in the MI/R group than in the sham group, and high UA levels worsened these changes. In vitro, cardiomyocytes viability was significantly downregulated, and the levels of ROS, LDH, pyroptosis-related protein, caspase-3, and the rate of cardiomyocyte death were significantly higher in the H/R + UA group compared with the HR group. Administration of an NLRP3 inflammasome inhibitor and ROS scavenger reversed these effects.Conclusion: UA aggravates MI/R-induced activation of the NLRP3 inflammatory cascade and pyroptosis by promoting ROS generation, while inflammasome inhibitors and ROS scavengers partly reverse the injury.