PMID- 22428064
OWN - NLM
STAT- MEDLINE
DCOM- 20120820
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 3
DP  - 2012
TI  - Local gene silencing of monocyte chemoattractant protein-1 prevents vulnerable 
      plaque disruption in apolipoprotein E-knockout mice.
PG  - e33497
LID - 10.1371/journal.pone.0033497 [doi]
LID - e33497
AB  - Monocyte chemoattractant protein-1 (MCP-1), a CC chemokine (CCL2), has been 
      demonstrated to play important roles in atherosclerosis and becoming an important 
      therapeutic target for atherosclerosis. The present study was undertaken to test 
      the hypothesis that local RNAi of MCP-1 by site-specific delivery of 
      adenovirus-mediated small hairpin RNA (shRNA) may enhance plaque stability and 
      prevent plaque disruption in ApoE-/- mice. We designed an adenovirus-mediated 
      shRNA against mouse MCP-1 (rAd5-MCP-1-shRNA). Male apolipoprotein E-knockout 
      (ApoE-/-) mice (n = 120) were fed a high-fat diet and vulnerable plaques were 
      induced by perivascular placement of constrictive collars around the carotid 
      artery, intraperitoneal injection of lipopolysaccharide and stress stimulation. 
      Mice were randomly divided into RNA interference (Ad-MCP-1i) group receiving 
      local treatment of rAd5-MCP-1-shRNA suspension, Ad-EGFP group receiving treatment 
      of rAd5-mediated negative shRNA and mock group receiving treatment of saline. Two 
      weeks after treatment, plaque disruption rates were significantly lower in the 
      Ad-MCP-1i group than in the Ad-EGFP group (13.3% vs. 60.0%, P = 0.01), and local 
      MCP-1 expression was significantly inhibited in the Ad-MCP-1i group confirmed by 
      immunostaining, qRT-PCR and western blot (P<0.001). Compared with the Ad-EGFP 
      group, carotid plaques in the Ad-MCP-1i group showed increased levels of collagen 
      and smooth muscle cells, and decreased levels of lipid and macrophages. The 
      expression of inflammatory cytokines and activities of matrix metalloproteinases 
      (MMPs) were lower in the Ad-MCP-1i group than in the Ad-EGFP group. In 
      conclusion, site-specific delivery of adenoviral-mediated shRNA targeting mouse 
      MCP-1 downregulated MCP-1 expression, turned a vulnerable plaque into a more 
      stable plaque phenotype and prevented plaque disruption. A marked suppression of 
      the local inflammatory cytokine expression may be the central mechanism involved.
FAU - Liu, Xiao Ling
AU  - Liu XL
AD  - Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese 
      Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong 
      University, Jinan, Shandong, China.
FAU - Zhang, Peng Fei
AU  - Zhang PF
FAU - Ding, Shi Fang
AU  - Ding SF
FAU - Wang, Yan
AU  - Wang Y
FAU - Zhang, Mei
AU  - Zhang M
FAU - Zhao, Yu Xia
AU  - Zhao YX
FAU - Ni, Mei
AU  - Ni M
FAU - Zhang, Yun
AU  - Zhang Y
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120312
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Apolipoproteins E)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Cytokines)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (enhanced green fluorescent protein)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - EC 3.4.24.- (Matrix Metalloproteinases)
SB  - IM
MH  - Acute Coronary Syndrome/*prevention & control
MH  - Animals
MH  - Apolipoproteins E/genetics
MH  - Blotting, Western
MH  - Case-Control Studies
MH  - Chemokine CCL2/genetics/*metabolism
MH  - Cytokines/metabolism
MH  - Green Fluorescent Proteins/metabolism
MH  - Male
MH  - Matrix Metalloproteinases/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Plaque, Atherosclerotic/*metabolism
MH  - RNA Interference
MH  - RNA, Small Interfering/genetics
MH  - Real-Time Polymerase Chain Reaction
PMC - PMC3299803
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/03/20 06:00
MHDA- 2012/08/21 06:00
PMCR- 2012/03/12
CRDT- 2012/03/20 06:00
PHST- 2012/01/09 00:00 [received]
PHST- 2012/02/11 00:00 [accepted]
PHST- 2012/03/20 06:00 [entrez]
PHST- 2012/03/20 06:00 [pubmed]
PHST- 2012/08/21 06:00 [medline]
PHST- 2012/03/12 00:00 [pmc-release]
AID - PONE-D-12-00837 [pii]
AID - 10.1371/journal.pone.0033497 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(3):e33497. doi: 10.1371/journal.pone.0033497. Epub 2012 Mar 12.