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. This evidence concerns the gene NR3C2 and familial hypercholesterolemia.