By using Smpd1trg/ECcre mice and the primary cultures of their ECs, our findings provide the first direct evidence that ASM-ceramide-MR redox signaling and downstream redox sensor TXNIP are involved in the formation and activation of NLRP3 inflammasome activation and subsequent neointimal hyperplasia during hypercholesterolemia. Here, NR3C2 is linked to Hypercholesterolemia.