PMID- 15838486
OWN - NLM
STAT- MEDLINE
DCOM- 20050512
LR  - 20220316
IS  - 0741-5214 (Print)
IS  - 0741-5214 (Linking)
VI  - 41
IP  - 3
DP  - 2005 Mar
TI  - Antisense to transforming growth factor-beta1 messenger RNA reduces vein graft 
      intimal hyperplasia and monocyte chemotactic protein 1.
PG  - 498-508
AB  - BACKGROUND: Autogenous vein grafts are commonly used for arterial reconstructive 
      procedures. Their success is limited by the development of intimal hyperplasia 
      (IH), a fibroproliferative disease that predisposes the grafts to occlusive 
      stenosis. Mesenchymal cell proliferation and the deposition of an extracellular 
      matrix characterize neointimal development. Increasing evidence suggests that, 
      regardless of blood vessel type, IH results from complex interactions among 
      vessel wall cells, infiltrating leukocytes, and cytokines. Transforming growth 
      factor-beta1 (TGF-beta1) is a pleiotropic cytokine with powerful effects on 
      inflammatory cell chemotaxis; smooth muscle cell, fibroblast, and endothelial 
      cell proliferation; and extracellular matrix synthesis. METHODS: Epigastric vein 
      to common femoral artery interposition grafts were placed in male Lewis rats and 
      harvested at 1, 2, 4, and 12 weeks after surgery. We used replication-defective 
      adenoviruses to deliver a control reporter gene for the enzyme beta-galactosidase 
      (Ad-GAL), empty virus (Ad-CMVpLpA), or the sequence encoding the antisense strand 
      of TGF-beta1 (Ad-AST). The vein graft was transduced passively in medium 
      containing 10 7 plaque-forming units per milliliter of Ad-GAL, Ad-CMVpLpA, or 
      Ad-AST for 20 minutes at room temperature. The adenovirus-treated grafts were 
      compared with grafts treated with medium without virus (sham). RESULTS: The 
      Ad-GAL control grafts showed beta-galactosidase activity from 3 days to 4 weeks. 
      Twenty percent of cells were positive out to 2 weeks, at which time the number of 
      cells positive for beta-galactosidase activity began to decline. Treatment with 
      Ad-AST resulted in a significant reduction vs sham, Ad-CMVpLpA, and Ad-GAL in 
      TGF-beta1 messenger RNA, total TGF-beta1 protein, and bioactive TGF-beta1 
      protein. Neointimal area was significantly reduced in the Ad-AST group vs Ad-GAL 
      at 4 weeks, vs Ad-CMVpLpA at 4 and 12 weeks, and vs sham at 2 and 4 weeks. The 
      medial/adventitial layer was significantly thicker in the Ad-AST group than the 
      Ad-GAL group at 12 weeks. In addition, we studied the effect of Ad-AST on 
      monocyte chemotactic protein 1 (MCP-1). Although the reduction in TGF-beta1 
      resulted in a reduction of MCP-1 messenger RNA in whole-graft homogenates and 
      MCP-1 protein-positive staining in histologic sections from the perianastomotic 
      region, no reduction in the number of ED1-positive cells (monocytes and 
      macrophages) was observed. CONCLUSIONS: Perioperative antisense TGF-beta1 
      treatment of the vein to be used in arterial reconstructions resulted in a 
      prolonged diminution of IH; this emphasizes the importance of TGF-beta1 in 
      neointimal thickening and indicates that ex vivo gene therapy can reduce the 
      vessel's predisposition to IH. CLINICAL RELEVANCE: The main cause of occlusion 
      and graft failure after peripheral and cardiac arterial reconstruction is IH. The 
      study of the mechanisms and mediators of IH, including TGF-beta1, should lead to 
      future gene therapies to prevent or limit IH. The clinical effect of such 
      treatments would be enormous, because they would increase graft longevity, 
      thereby enhancing quality of life and enabling patients to live without the 
      threat of limb loss or recurrent heart attack.
FAU - Wolff, Randal A
AU  - Wolff RA
AD  - Department of Surgery, Medical School, University of Wisconsin-Madison, 600 
      Highland Avenue, Madison, WI 53792, USA.
FAU - Ryomoto, Masaaki
AU  - Ryomoto M
FAU - Stark, V Emily
AU  - Stark VE
FAU - Malinowski, Rita
AU  - Malinowski R
FAU - Tomas, Jeffrey J
AU  - Tomas JJ
FAU - Stinauer, Michelle A
AU  - Stinauer MA
FAU - Hullett, Debra A
AU  - Hullett DA
FAU - Hoch, John R
AU  - Hoch JR
LA  - eng
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - J Vasc Surg
JT  - Journal of vascular surgery
JID - 8407742
RN  - 0 (Chemokine CCL2)
RN  - 0 (RNA, Antisense)
RN  - 0 (Transforming Growth Factor beta)
SB  - IM
MH  - Adenoviridae/genetics
MH  - Animals
MH  - Chemokine CCL2/*metabolism
MH  - Extracellular Matrix/metabolism
MH  - Gene Transfer Techniques
MH  - Graft Occlusion, Vascular/prevention & control
MH  - Hyperplasia
MH  - Immunohistochemistry
MH  - RNA, Antisense/pharmacology/*therapeutic use
MH  - Rats
MH  - Transforming Growth Factor beta/*physiology
MH  - Tunica Intima/pathology
MH  - Veins/*transplantation
MH  - Wound Healing/genetics/physiology
EDAT- 2005/04/20 09:00
MHDA- 2005/05/13 09:00
CRDT- 2005/04/20 09:00
PHST- 2005/04/20 09:00 [pubmed]
PHST- 2005/05/13 09:00 [medline]
PHST- 2005/04/20 09:00 [entrez]
AID - S0741521404017112 [pii]
AID - 10.1016/j.jvs.2004.12.037 [doi]
PST - ppublish
SO  - J Vasc Surg. 2005 Mar;41(3):498-508. doi: 10.1016/j.jvs.2004.12.037.