Glycogen synthase kinase-3β inhibition alleviates NLRP3 inflammasome activation in myocardial infarction

OBJECTIVE To investigate the regulatory mechanisms of glycogen synthase kinase-3β(GSK-3β)on NLRP3 inflammasome activation. METHODS We conducted myocardial infarction(MI) model in male Sprague-Dawley(SD) rat during days 2-28. An in vitro investigation was performed using new-born rat/human cardiomyocyte and fibroblast cultures under typical inflammasome stimulation and hypoxia treatment. Further identification for possibility of GSK-3β active NLRP3 inflammasomes, GSK-3β immunoprecipitation was performed from the lysate of inflammasome stimulation-treated rat neonatal fibroblasts(RCFs) with or without GSK-3β inhibitor pretreatment. RESULTS Assessments of cardiac function, histochemical and biochemical assays for cardiac tissues, as well as detection of protein and m RNA expressions in heart tissues, showed that GSK-3β inhibition remarkably improves myocardial dysfunction and prevents remodeling with parallel reduction of the parameters of NLRP3 inflammasome activation after MI. The measurement of primary rats/human cells expounded that GSK-3β inhibition reduce NLRP3 inflammasome activation happens in cardiac fibroblasts, but not in cardiomyocytes. Futhermore, GSK-3β interacts with ASC and GSK-3β inhibition reduces cytoplasmic aggregates of ASC, NLRP3 and caspase-1 formation. CONCLUSION GSK-3β directly mediates NLRP3 inflammasome activation causing cardiac dysfunction in MI.