PMID- 18266972
OWN - NLM
STAT- MEDLINE
DCOM- 20090402
LR  - 20211020
IS  - 1582-1838 (Print)
IS  - 1582-4934 (Electronic)
IS  - 1582-1838 (Linking)
VI  - 12
IP  - 6A
DP  - 2008 Dec
TI  - Dominant-negative mutation of monocyte chemoattractant protein-1 prevents 
      vulnerable plaques from rupture in rabbits independent of serum lipid levels.
PG  - 2362-71
LID - 10.1111/j.1582-4934.2008.00261.x [doi]
AB  - Active inflammation is an important feature of vulnerable plaques, and monocyte 
      chemoattractant protein-1 (MCP-1) is a key chemokine that promotes 
      monocyte-endothelium binding and initiates inflammation. We aimed to determine 
      whether dominant-negative mutation of MCP-1 could reverse atherosclerotic lesion 
      progression and prevent vulnerable plaques from rupture regardless of serum lipid 
      levels. The mutant MCP-1 was produced by deletion of the N-terminal amino acids 2 
      to 8 (7ND), and a eukaryotic expression vector plRES-EGFP-7ND was constructed. 
      The transwell chamber was used to assay chemotaxis of monocytes in vitro. Thirty 
      New Zealand white rabbits underwent balloon-induced abdominal aortic endothelial 
      injury and were randomly divided into control group without gene intervention 
      (group A, n=10), plRES-EGFP-7ND treatment group (group B, n=10) and empty vector 
      treatment group (group C, n=10). All rabbits were fed a diet of 1% cholesterol 
      for 8 weeks, and then group A rabbits were killed, whereas groups B and C rabbits 
      received an intramuscular injection of plRES-EGFP-7ND and an empty lipofectamine, 
      respectively, and remained on a high cholesterol diet for 4 weeks. At the end of 
      week 12, groups B and C rabbits underwent pharmacological triggering by injection 
      with Chinese Russellis viper venom and histamine. Serum lipids and inflammatory 
      markers were measured, and high-frequency ultra-sonography and intravascular 
      ultrasound imaging were performed. Immunohistochemistry and RT-PCR were used to 
      examine expression of inflammatory markers in the plaques. In vitro transfection 
      of plRES-EGFP-7ND resulted in a significant inhibition of monocyte chemotaxis 
      (P<0.05) and in vivo transfection of plRES-EGFP-7ND significantly increased the 
      thickness of the fibrous caps and decreased plaque vulnerability index. The 
      incidence of plaque rupture in group B was 0% as compared with 56% in the empty 
      vector treatment group (P<0.05). The serum levels and expression of inflammatory 
      markers were significantly reduced in group B. In conclusion, PIRES-EGFP-7ND 
      transfection effectively inhibits plaque inflammation, reverses plaque 
      progression and prevents vulnerable plaques from rupture. These therapeutic 
      effects are independent of serum lipid levels and demonstrate that inhibition of 
      plaque inflammation alone without lipid lowering can stabilize vulnerable 
      plaques.
FAU - Zhong, Lin
AU  - Zhong L
AD  - The Key Laboratory of Cardiovascular Remodelling and Function Research, Chinese 
      Ministry of Education and Chinese Ministry of Health, Shandong University Qilu 
      Hospital, Jinan, Shandong, China.
FAU - Chen, Wen Qiang
AU  - Chen WQ
FAU - Ji, Xiao Ping
AU  - Ji XP
FAU - Zhang, Mei
AU  - Zhang M
FAU - Zhao, Yu Xia
AU  - Zhao YX
FAU - Yao, Gui Hua
AU  - Yao GH
FAU - Zhang, Peng Fei
AU  - Zhang PF
FAU - Zhang, Cheng
AU  - Zhang C
FAU - Zhang, Yun
AU  - Zhang Y
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080204
PL  - England
TA  - J Cell Mol Med
JT  - Journal of cellular and molecular medicine
JID - 101083777
RN  - 0 (Chemokine CCL2)
RN  - 0 (Lipids)
SB  - IM
MH  - Animals
MH  - Atherosclerosis/*blood/*genetics/pathology/therapy
MH  - Chemokine CCL2/antagonists & inhibitors/*genetics
MH  - Chemotaxis, Leukocyte
MH  - Gene Expression
MH  - Humans
MH  - In Vitro Techniques
MH  - Lipids/*blood
MH  - Male
MH  - Monocytes/physiology
MH  - *Mutation
MH  - Rabbits
MH  - Sequence Deletion
MH  - Transfection
PMC - PMC4514114
EDAT- 2008/02/13 09:00
MHDA- 2009/04/03 09:00
PMCR- 2008/12/01
CRDT- 2008/02/13 09:00
PHST- 2008/02/13 09:00 [pubmed]
PHST- 2009/04/03 09:00 [medline]
PHST- 2008/02/13 09:00 [entrez]
PHST- 2008/12/01 00:00 [pmc-release]
AID - JCMM261 [pii]
AID - 10.1111/j.1582-4934.2008.00261.x [doi]
PST - ppublish
SO  - J Cell Mol Med. 2008 Dec;12(6A):2362-71. doi: 10.1111/j.1582-4934.2008.00261.x. 
      Epub 2008 Feb 4.