NR1D1 Deletion Induces Rupture-Prone Vulnerable Plaques by Regulating Macrophage Pyroptosis via the NF-κB/NLRP3 Inflammasome Pathway

Vulnerable plaque rupture is the main trigger of most acute cardiovascular events. But the underlying mechanisms responsible for the transition from stable to vulnerable plaque remain largely unknown. Nuclear receptor subfamily 1 group D member 1 (NR1D1), also known as REV-ERB alpha, is a nuclear receptor that has shown the protective role in cardiovascular system. However, the effect of NR1D1 on vulnerable plaque rupture and its underlying mechanisms are still unclear. By generating the rupture-prone vulnerable plaque model in hypercholesterolemic ApoE(-/-) mice and NR1D1(-/-)ApoE(-/-) mice, we demonstrated that NR1D1 deficiency significantly augmented plaque vulnerability/rupture, with higher incidence of intraplaque hemorrhage (78.26% vs. 47.82%, P=0.0325) and spontaneous plaque rupture with intraluminal thrombus formation (65.21% vs. 39.13%, P=0.1392). In vivo experiments indicated that NR1D1 exerted a protective role in the vasculature. Mechanically, NR1D1 deficiency aggravates macrophage infiltration, inflammation, and oxidative stress. Compared with the ApoE(-/-) mice, NR1D1(-/-)ApoE(-/-) mice exhibited a significantly higher expression level of pyroptosis-related genes in macrophages within the plaque. Further investigation based on mice bone marrow-derived macrophages (BMDMs) confirmed that NR1D1 exerted a protective effect by inhibiting macrophage pyroptosis in a NLRP3-inflammasome-dependent manner. Besides, pharmacological activation of NR1D1 by SR9009, a specific NR1D1 agonist, prevented plaque vulnerability/rupture. In general, our findings provide further evidences that NR1D1 plays a protective role in the vasculature, regulates inflammation and oxidative stress, and stabilizes rupture-prone vulnerable plaques.

Automated summary

NR1D1 deficiency exacerbates plaque vulnerability/rupture by promoting macrophage infiltration, inflammation, and oxidative stress, while NR1D1 activation through a specific agonist can prevent plaque vulnerability/rupture. Additionally, NR1D1 plays a protective role in the vasculature and stabilizes rupture-prone vulnerable plaques by inhibiting macrophage pyroptosis.