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.

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.

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.

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.