PMID- 35954287
OWN - NLM
STAT- MEDLINE
DCOM- 20220815
LR  - 20221106
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 11
IP  - 15
DP  - 2022 Aug 6
TI  - HHcy Induces Pyroptosis and Atherosclerosis via the Lipid Raft-Mediated 
      NOX-ROS-NLRP3 Inflammasome Pathway in apoE(-/-) Mice.
LID - 10.3390/cells11152438 [doi]
LID - 2438
AB  - Lipid rafts play important roles in signal transduction, particularly in 
      responses to inflammatory processes. The current study aimed to identify whether 
      lipid raft-mediated inflammation contributes to hyperhomocysteinemia 
      (HHcy)-accelerated atherosclerosis (AS), and to investigate the underlying 
      mechanisms. THP-1-derived macrophages were used for in vitro experiments. 
      ApoE(-/-) mice were fed a high-fat diet for 12 weeks to establish an AS model, 
      and a high-fat plus high-methionine diet was used to induce HHcy. We found that 
      homocysteine (Hcy) increased the expression of p22(phox) and p67(phox) and 
      promoted their recruitment into lipid rafts (indicating the assembly of the NOX 
      complex), thereby increasing ROS generation and NOX activity, NLRP3 inflammasome 
      activation, and pyroptosis. Mechanistically, Hcy activated the NOX-ROS-NLRP3 
      inflammasome pathway and induced pyroptosis by increasing the expression of acid 
      sphingomyelinase (ASM) to promote the formation of lipid raft clustering. 
      Importantly, lipid raft-mediated pyroptosis was confirmed in HHcy mice, and 
      HHcy-promoted macrophage recruitment in atherosclerotic lesions and 
      HHcy-aggravated AS were blocked by the lipid raft disruptor 
      methyl-beta-cyclodextrin. The study findings indicate that Hcy promotes lipid raft 
      clustering via the upregulation of ASM, which mediates the assembly of the NOX 
      complex, causing an increase in ROS generation, NLRP3 inflammasome activation, 
      and pyroptosis, and contributes to HHcy-induced AS.
FAU - Liu, Sijun
AU  - Liu S
AD  - Department of Pathophysiology, School of Medicine, Sun Yat-sen University, 
      Shenzhen 518107, China.
AD  - Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen 
      University, Guangzhou 510080, China.
FAU - Tao, Jun
AU  - Tao J
AD  - Department of Pathophysiology, School of Medicine, Sun Yat-sen University, 
      Shenzhen 518107, China.
AD  - Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen 
      University, Guangzhou 510080, China.
FAU - Duan, Fengqi
AU  - Duan F
AD  - Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen 
      University, Guangzhou 510080, China.
FAU - Li, Huangjing
AU  - Li H
AD  - Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen 
      University, Guangzhou 510080, China.
FAU - Tan, Hongmei
AU  - Tan H
AD  - Department of Pathophysiology, School of Medicine, Sun Yat-sen University, 
      Shenzhen 518107, China.
AD  - Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen 
      University, Guangzhou 510080, China.
AD  - Laboratory Animal Center, Sun Yat-sen University, Guangzhou 510080, China.
AD  - Department of Endocrinology, the Third Affiliated Hospital of Sun Yat-sen 
      University, Guangzhou 510630, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220806
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (Apolipoproteins E)
RN  - 0 (Inflammasomes)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (Nlrp3 protein, mouse)
RN  - 0 (Reactive Oxygen Species)
SB  - IM
MH  - Animals
MH  - Apolipoproteins E
MH  - *Atherosclerosis/metabolism
MH  - *Hyperhomocysteinemia/metabolism
MH  - Inflammasomes/metabolism
MH  - Membrane Microdomains/metabolism
MH  - Mice
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
MH  - Pyroptosis
MH  - Reactive Oxygen Species/metabolism
PMC - PMC9368640
OTO - NOTNLM
OT  - NLRP3 inflammasome
OT  - NOX
OT  - atherosclerosis
OT  - lipid rafts
OT  - pyroptosis
COIS- The authors declare no conflict of interest.
EDAT- 2022/08/13 06:00
MHDA- 2022/08/16 06:00
PMCR- 2022/08/06
CRDT- 2022/08/12 01:04
PHST- 2022/07/03 00:00 [received]
PHST- 2022/07/31 00:00 [revised]
PHST- 2022/08/03 00:00 [accepted]
PHST- 2022/08/12 01:04 [entrez]
PHST- 2022/08/13 06:00 [pubmed]
PHST- 2022/08/16 06:00 [medline]
PHST- 2022/08/06 00:00 [pmc-release]
AID - cells11152438 [pii]
AID - cells-11-02438 [pii]
AID - 10.3390/cells11152438 [doi]
PST - epublish
SO  - Cells. 2022 Aug 6;11(15):2438. doi: 10.3390/cells11152438.