P65/NLRP3 Inflammasome Mediated Endothelial Cells Pyroptosis: A Novel Mechanism of In-Stent Restenosis

Abstract

Background: In-stent restenosis (ISR) is one of the key causes of ischemic events after coronary stent implantation, and endothelial cell death and inflammation are considered to be important mechanisms. Pyroptosis is a proinflammatory type of programmed cell death, the effects and underlying mechanisms of endothelial cell (EC) pyroptosis in ISR remains unclear. Method: According to our previous work, an ISR rabbit model was established. Rabbits were divided into sham operation group and stent group. Serum was collected at 0, 4, 8, and 12 weeks to detect interleukin (IL)-1β and IL-18 levels. Rabbits' vascular EC was collected to detect NLRP3, Caspase1, GSDMD and P65 expression by western blot. NLRP3 inhibitor (MCC950) and P65 inhibitor (Helenalin) were used to pretreat EC, cell viability, lactate dehydrogenase (LDH) level of supernatant and pyroptosis related protein expression were measured in different groups. Results: The serum levels of IL-1β and IL-18 gradually increased with time, and the levels at the site of stent implantation were higher than the peripheral level. EC viability decreased significantly in the stent group, and protein levels of NLRP3, caspase1 and GSDMD were higher than those in the sham group. MCC950 and P65 inhibitors can reverse these effects. Conclusions: EC pyroptosis mediated by P65/NLRP3 inflammasome axis may promote ISR, our results provide a potential intervention target for the treatment of ISR.