期刊
BIOMEDICINE & PHARMACOTHERAPY
卷 133, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biopha.2020.110990
关键词
Uric acid; Myocardial ischemia-reperfusion; Reactive oxygen species; NLRP3 inflammasome; Pyroptosis
资金
- Anhui Provincial Natural Science Foundation [1808085QH235]
- Youth Elites Support Plan in universities of Anhui Province [gxyq2019013]
- Excellent Young Talents Fund Program of Higher Education Institutions of Anhui Province [gxgwfx2019010]
This study revealed that uric acid exacerbates MI/R injury by promoting ROS generation, while NLRP3 inflammasome inhibitors and ROS scavengers partially reverse this injury.
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.
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