PMID- 34956438
OWN - NLM
STAT- MEDLINE
DCOM- 20220303
LR  - 20220303
IS  - 1942-0994 (Electronic)
IS  - 1942-0900 (Print)
IS  - 1942-0994 (Linking)
VI  - 2021
DP  - 2021
TI  - NR1D1 Deletion Induces Rupture-Prone Vulnerable Plaques by Regulating Macrophage 
      Pyroptosis via the NF-kappaB/NLRP3 Inflammasome Pathway.
PG  - 5217572
LID - 10.1155/2021/5217572 [doi]
LID - 5217572
AB  - 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.
CI  - Copyright (c) 2021 Zhinan Wu et al.
FAU - Wu, Zhinan
AU  - Wu Z
AUID- ORCID: 0000-0002-3219-1994
AD  - Department of Cardiology, Renji Hospital, Shanghai Jiao Tong University School of 
      Medicine, Shanghai, China.
FAU - Liao, Fei
AU  - Liao F
AUID- ORCID: 0000-0001-9182-634X
AD  - Department of Cardiology, Renji Hospital, Shanghai Jiao Tong University School of 
      Medicine, Shanghai, China.
FAU - Luo, Guqing
AU  - Luo G
AUID- ORCID: 0000-0002-1047-4387
AD  - Department of Cardiology, Renji Hospital, Shanghai Jiao Tong University School of 
      Medicine, Shanghai, China.
FAU - Qian, Yuxuan
AU  - Qian Y
AUID- ORCID: 0000-0002-0164-732X
AD  - Department of Cardiology, Renji Hospital, Shanghai Jiao Tong University School of 
      Medicine, Shanghai, China.
FAU - He, Xinjie
AU  - He X
AUID- ORCID: 0000-0002-1810-4209
AD  - Department of Cardiology, Renji Hospital, Shanghai Jiao Tong University School of 
      Medicine, Shanghai, China.
FAU - Xu, Wenyi
AU  - Xu W
AUID- ORCID: 0000-0002-6588-675X
AD  - Department of Cardiology, Renji Hospital, Shanghai Jiao Tong University School of 
      Medicine, Shanghai, China.
FAU - Ding, Song
AU  - Ding S
AUID- ORCID: 0000-0003-0618-9388
AD  - Department of Cardiology, Renji Hospital, Shanghai Jiao Tong University School of 
      Medicine, Shanghai, China.
FAU - Pu, Jun
AU  - Pu J
AUID- ORCID: 0000-0002-4337-4649
AD  - Department of Cardiology, Renji Hospital, Shanghai Jiao Tong University School of 
      Medicine, Shanghai, China.
LA  - eng
PT  - Journal Article
DEP - 20211216
PL  - United States
TA  - Oxid Med Cell Longev
JT  - Oxidative medicine and cellular longevity
JID - 101479826
RN  - 0 (Inflammasomes)
RN  - 0 (NF-kappa B)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (Nr1d1 protein, mouse)
RN  - 0 (Nuclear Receptor Subfamily 1, Group D, Member 1)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Inflammasomes/*metabolism
MH  - Macrophages/*metabolism
MH  - Male
MH  - Mice
MH  - NF-kappa B/*metabolism
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/*metabolism
MH  - Nuclear Receptor Subfamily 1, Group D, Member 1/*metabolism
MH  - Pyroptosis/*physiology
PMC - PMC8702349
COIS- The authors declare that they have no conflicts of interest.
EDAT- 2021/12/28 06:00
MHDA- 2022/03/04 06:00
PMCR- 2021/12/16
CRDT- 2021/12/27 06:27
PHST- 2021/10/14 00:00 [received]
PHST- 2021/11/11 00:00 [accepted]
PHST- 2021/12/27 06:27 [entrez]
PHST- 2021/12/28 06:00 [pubmed]
PHST- 2022/03/04 06:00 [medline]
PHST- 2021/12/16 00:00 [pmc-release]
AID - 10.1155/2021/5217572 [doi]
PST - epublish
SO  - Oxid Med Cell Longev. 2021 Dec 16;2021:5217572. doi: 10.1155/2021/5217572. 
      eCollection 2021.