PMID- 28394319
OWN - NLM
STAT- MEDLINE
DCOM- 20170828
LR  - 20230216
IS  - 1530-0307 (Electronic)
IS  - 0023-6837 (Print)
IS  - 0023-6837 (Linking)
VI  - 97
IP  - 8
DP  - 2017 Aug
TI  - Activation of NLRP3 inflammasomes contributes to hyperhomocysteinemia-aggravated 
      inflammation and atherosclerosis in apoE-deficient mice.
PG  - 922-934
LID - 10.1038/labinvest.2017.30 [doi]
AB  - Hyperhomocysteinemia (HHcy) has been shown to promote vascular inflammation and 
      atherosclerosis, but the underlying mechanisms remain largely unknown. The NLRP3 
      inflammasome has been identified as the cellular machinery responsible for 
      activation of inflammatory processes. In this study, we hypothesized that the 
      activation of NLRP3 inflammasomes contributes to HHcy-induced inflammation and 
      atherosclerosis. ApoE(-/-) mice were fed regular chow, high-fat (HF) diet, or HF 
      plus high methionine diet to induce HHcy. To assess the role of NLRP3 
      inflammasomes in HHcy-aggravated atherosclerosis, NLRP3 shRNA viral suspension 
      was injected via tail vein to knock down the NLRP3 gene. Increased plasma levels 
      of IL-1beta and IL-18, aggravated macrophage infiltration into atherosclerotic 
      lesions, and accelerated development of atherosclerosis were detected in HHcy 
      mice as compared with control mice, and were associated with the activation of 
      NLRP3 inflammasomes. Silencing the NLRP3 gene significantly suppressed NLRP3 
      inflammasome activation, reduced plasma levels of proinflammatory cytokines, 
      attenuated macrophage infiltration and improved HHcy-induced atherosclerosis. We 
      also examined the effect of homocysteine (Hcy) on NLRP3 inflammasome activation 
      in THP-1-differentiated macrophages in the presence or absence of NLRP3 siRNA or 
      the caspase-1 inhibitor Z-WEHD-FMK. We found that Hcy activated NLRP3 
      inflammasomes and promoted subsequent production of IL-1beta and IL-18 in 
      macrophages, which were blocked by NLRP3 gene silencing or Z-WEHD-FMK. As 
      reactive oxygen species (ROS) may have a central role in NLRP3 inflammasome 
      activation, we next investigated whether antioxidant N-acetyl-l-cysteine (NAC) 
      prevented Hcy-induced NLRP3 inflammasome activation in macrophages. We found 
      Hcy-induced NLRP3 inflammasome activation was abolished by NAC. Treatment with 
      NAC in HHcy mice also suppressed NLRP3 inflammasome activation and improved 
      HHcy-induced atherosclerosis. These data suggest that the activation of NLRP3 
      inflammasomes contributes to HHcy-aggravated inflammation and atherosclerosis in 
      apoE(-/-) mice. Hcy activates NLRP3 inflammasomes in ROS-dependent pathway in 
      macrophages. These results may have implication for the treatment of 
      HHcy-associated cardiovascular diseases.
FAU - Wang, Renqing
AU  - Wang R
AD  - Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen 
      University, Guangzhou, China.
FAU - Wang, Yiqin
AU  - Wang Y
AD  - Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen 
      University, Guangzhou, China.
FAU - Mu, Nana
AU  - Mu N
AD  - Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen 
      University, Guangzhou, China.
FAU - Lou, Xiaoying
AU  - Lou X
AD  - Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen 
      University, Guangzhou, China.
FAU - Li, Weixuan
AU  - Li W
AD  - Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen 
      University, Guangzhou, China.
FAU - Chen, Yanming
AU  - Chen Y
AD  - Division of Endocrinology, Third Affiliated Hospital, Sun Yat-sen University, 
      Guangzhou, China.
FAU - Fan, Dong
AU  - Fan D
AD  - Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen 
      University, Guangzhou, China.
FAU - Tan, Hongmei
AU  - Tan H
AD  - Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen 
      University, Guangzhou, China.
AD  - Guangdong Engineering and Technology Research Center for Disease-Model Animals, 
      Sun Yat-sen University, Guangzhou, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170410
PL  - United States
TA  - Lab Invest
JT  - Laboratory investigation; a journal of technical methods and pathology
JID - 0376617
RN  - 0 (Apolipoproteins E)
RN  - 0 (Inflammasomes)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (Nlrp3 protein, mouse)
SB  - IM
MH  - Animals
MH  - Apolipoproteins E/*genetics
MH  - Atherosclerosis/*metabolism
MH  - Cell Line, Tumor
MH  - Humans
MH  - Hyperhomocysteinemia/*metabolism
MH  - Inflammasomes/*metabolism
MH  - Inflammation/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/genetics/*metabolism
PMC - PMC5537437
COIS- The authors declare no conflict of interest.
EDAT- 2017/04/11 06:00
MHDA- 2017/08/29 06:00
PMCR- 2017/08/01
CRDT- 2017/04/11 06:00
PHST- 2016/07/08 00:00 [received]
PHST- 2017/02/05 00:00 [revised]
PHST- 2017/02/06 00:00 [accepted]
PHST- 2017/04/11 06:00 [pubmed]
PHST- 2017/08/29 06:00 [medline]
PHST- 2017/04/11 06:00 [entrez]
PHST- 2017/08/01 00:00 [pmc-release]
AID - S0023-6837(22)00423-8 [pii]
AID - 10.1038/labinvest.2017.30 [doi]
PST - ppublish
SO  - Lab Invest. 2017 Aug;97(8):922-934. doi: 10.1038/labinvest.2017.30. Epub 2017 Apr 
      10.