ENDOPLASMIC RETICULUM STRESS-INDUCED NLRP1 INFLAMMASOME ACTIVATION CONTRIBUTES TO MYOCARDIAL ISCHEMIA/REPERFUSION INJURY

Studies have shown that Nod-like receptor protein (NLRP) 3 inflammasome activation contributes to myocardial ischemia/reperfusion (I/R) injury. However, the role and mechanism of NLRP1 inflammasome in myocardial I/R injury remain unknown. Endoplasmic reticulum (ER) stress is involved in the development of myocardial I/R injury. The relationship between ER stress and NLRP1 inflammasome in myocardial I/R injury needs further study. NLRP1 inflammasome activation and ER stress were investigated in hypoxia/reoxygenation (H/R)-treated primary mouse cardiomyocytes and left anterior descending coronary artery ligation and reperfusion mouse models. Downregulation of NLRP1 expression with NLRP1 small interfering RNA (siRNA) was used to evaluate the role of NLRP1 inflammasome in H/R-stimulated cardiomyocyte injury. 4-phenylbutyric acid (4-PBA), an ER stress inhibitor, was used to pretreat cardiomyocytes before H/R treatment, the cardiomyocyte injury and NLRP1 inflammasome activation were determined. Also, nuclear factor (NF)-kappa B signaling activity was measured. Additionally, pyrrolidine dithiocar bamate (PDTC), an NF-kappa B inhibitor, was used to treat cardiomyocytes before H/R stimulation and NLRP1 inflammasome activation was examined. We found the levels of ER stress markers GRP78, p-PERK, p-eIF2 alpha and CHOP as well as NLRP1 inflammasome activation were significantly elevated both in vivo and in vitro. NLRP1 siRNA notably increased cell viability inhibited by H/R, suppressed H/R-induced cell apoptosis, lactate dehydrogenase release, and creatine kinase activity. 4-PBA reduced H/R-stimulated cardiomyocyte injury via NLRP1 inflammasome inactivation, and it also suppressed NF-kappa B signaling activity. NLRP1 inflammasome activation induced by H/R was also suppressed by PDTC. In conclusion, NLRP1 inflammasome activation promotes myocardial I/R injury. ER stress can activate NLRP1 inflammasome via activating the NF-kappa B signaling pathway.