PMID- 19563963
OWN - NLM
STAT- MEDLINE
DCOM- 20090709
LR  - 20121003
IS  - 1097-6809 (Electronic)
IS  - 0741-5214 (Linking)
VI  - 50
IP  - 1
DP  - 2009 Jul
TI  - Local lentiviral short hairpin RNA silencing of CCR2 inhibits vein graft 
      thickening in hypercholesterolemic apolipoprotein E3-Leiden mice.
PG  - 152-60
LID - 10.1016/j.jvs.2009.03.027 [doi]
AB  - OBJECTIVE: Inflammatory responses to vascular injury are key events in vein graft 
      disease and accelerated atherosclerosis, which may result in bypass failure. The 
      monocyte chemoattractant protein-1 (MCP-1)/CC-chemokine receptor (CCR)-2 pathway 
      is hypothesized to play a central role. A murine model for vein graft disease was 
      used to study the effect of local application of lentiviral short hairpin RNA 
      (shRNA) targeted against CCR2. METHODS: A venous interposition was placed into 
      the carotid artery of hypercholesterolemic apolipoprotein E3-Leiden 
      (APOE*3-Leiden) mice to induce vein graft thickening with features of accelerated 
      atherosclerosis. To demonstrate the efficacy of the lentiviral shRNA targeting 
      murine CCR2 (shCCR2) in blocking vein graft disease in vivo, lentiviral shCCR2 or 
      a control lentivirus was used to infect the vein graft locally (n = 8). RESULTS: 
      Vascular CCR2 and MCP-1 messenger RNA expression levels were significantly 
      upregulated during lesion progression in the vein graft. Infection of smooth 
      muscle cells (SMCs) with a lentiviral shRNA targeting shCCR2 completely abolished 
      MCP-1-induced SMC migration and inhibited SMC proliferation in vitro (n = 3 per 
      group). Morphometric analysis of sections of grafts showed a significant 38% 
      reduction in vein graft thickening in the shCCR2-treated mice 4 weeks after 
      surgery (control, 0.42 +/- 0.05 mm(2); shCCR2, 0.26 +/- 0.03 mm(2); P = .007). 
      CONCLUSION: Vascular CCR2 contributes to vein graft disease, and local 
      application of shRNA against CCR2 to the vessel wall prevents vein graft 
      thickening in hypercholesterolemic mice, suggesting that local overexpressing of 
      shRNA using organ-targeted lentiviral gene delivery may be a promising 
      therapeutic tool to improve vein graft disease in bypassed patients. CLINICAL 
      RELEVANCE: Vein graft disease is an important clinical issue that results from an 
      inflammatory response. The monocyte chemoattractant protein (MCP)-1/CC-chemokine 
      receptor (CCR)-2 pathway plays a key role in the initiation and development of 
      vein graft disease. This study demonstrates that perivascular overexpression of 
      short hairpin RNA, targeted against CCR2, inhibits vein graft thickening. These 
      data show that organ-targeted gene therapy against CCR2 in the vessel wall could 
      be a promising therapeutic tool to improve vein graft patency in bypassed 
      patients.
FAU - Eefting, Daniel
AU  - Eefting D
AD  - Gaubius Laboratory, TNO Quality of Life, Leiden, The Netherlands.
FAU - Bot, Ilze
AU  - Bot I
FAU - de Vries, Margreet R
AU  - de Vries MR
FAU - Schepers, Abbey
AU  - Schepers A
FAU - van Bockel, J Hajo
AU  - van Bockel JH
FAU - Van Berkel, Theo J C
AU  - Van Berkel TJ
FAU - Biessen, Erik A L
AU  - Biessen EA
FAU - Quax, Paul H A
AU  - Quax PH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Vasc Surg
JT  - Journal of vascular surgery
JID - 8407742
RN  - 0 (Apolipoprotein E3)
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Ccr2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Receptors, CCR2)
RN  - 0 (apolipoprotein E3 (Leidein))
SB  - IM
MH  - Animals
MH  - Apolipoprotein E3
MH  - Atherosclerosis
MH  - Chemokine CCL2/genetics
MH  - Disease Models, Animal
MH  - Graft Occlusion, Vascular/etiology/*prevention & control
MH  - Hypercholesterolemia/*complications
MH  - Lentivirus
MH  - Male
MH  - Mice
MH  - *RNA Interference
MH  - Receptors, CCR2/*genetics
MH  - Veins/transplantation
EDAT- 2009/07/01 09:00
MHDA- 2009/07/10 09:00
CRDT- 2009/07/01 09:00
PHST- 2008/12/02 00:00 [received]
PHST- 2009/03/09 00:00 [revised]
PHST- 2009/03/14 00:00 [accepted]
PHST- 2009/07/01 09:00 [entrez]
PHST- 2009/07/01 09:00 [pubmed]
PHST- 2009/07/10 09:00 [medline]
AID - S0741-5214(09)00680-6 [pii]
AID - 10.1016/j.jvs.2009.03.027 [doi]
PST - ppublish
SO  - J Vasc Surg. 2009 Jul;50(1):152-60. doi: 10.1016/j.jvs.2009.03.027.