PMID- 15194054
OWN - NLM
STAT- MEDLINE
DCOM- 20050113
LR  - 20170120
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 9
IP  - 6
DP  - 2004 Jun
TI  - Potent inhibition of arterial intimal hyperplasia by TIMP1 gene transfer using 
      AAV vectors.
PG  - 876-84
AB  - Seminal to the process of arterial restenosis after balloon angioplasty is 
      extracellular matrix degradation by metalloproteinases (MMPs); activity of these 
      proteins is strongly inhibited by the tissue inhibitors of MMPs (TIMPs). Here we 
      exploit gene transfer using an adeno-associated virus (AAV) for TIMP1 gene 
      delivery in a rat model of intimal hyperplasia. High-titer AAV-Timp1 efficiently 
      transduced human coronary artery smooth muscle cells (SMCs) in vitro and 
      inhibited the capacity of these cells to migrate through a Matrigel barrier. In 
      injured rat carotid arteries, AAV vectors were found to transduce SMCs 
      efficiently and to maintain transgene expression for several weeks in vivo. In 
      AAV-Timp1-transduced animals, the intima:media ratio of injured carotids was 
      significantly reduced by 70.5% after 2 weeks, by 58.5% after 1 month, and by 
      52.4% after 2 months from treatment. The decrease in intimal hyperplasia was 
      paralleled by a significant inhibition of collagen accumulation and by increased 
      elastin deposition in the neointima, two findings that relate to the inhibition 
      of MMP activity. These results indicate that AAV vectors are efficient tools for 
      delivering genes to the arterial wall and emphasize the importance of MMPs for 
      the generation of intimal hyperplasia. Local TIMP1 gene transfer might thus 
      represent an efficient strategy to prevent restenosis.
FAU - Ramirez Correa, Genaro A
AU  - Ramirez Correa GA
AD  - Molecular Medicine Laboratory, International Center for Genetic Engineering and 
      Biotechnology, Padriciano 99, 34012 Trieste, Italy.
FAU - Zacchigna, Serena
AU  - Zacchigna S
FAU - Arsic, Nikola
AU  - Arsic N
FAU - Zentilin, Lorena
AU  - Zentilin L
FAU - Salvi, Alessandro
AU  - Salvi A
FAU - Sinagra, Gianfranco
AU  - Sinagra G
FAU - Giacca, Mauro
AU  - Giacca M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (Matrix Metalloproteinase Inhibitors)
RN  - 0 (Tissue Inhibitor of Metalloproteinase-1)
RN  - 9007-34-5 (Collagen)
RN  - 9007-58-3 (Elastin)
RN  - EC 3.4.24.24 (Matrix Metalloproteinase 2)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
SB  - IM
MH  - Angioplasty, Balloon/adverse effects
MH  - Animals
MH  - Arterial Occlusive Diseases/etiology/pathology/*therapy
MH  - Carotid Arteries/enzymology/pathology
MH  - Collagen/analysis
MH  - Dependovirus/*genetics
MH  - Elastin/analysis
MH  - Genetic Therapy/*methods
MH  - Genetic Vectors/genetics
MH  - Humans
MH  - Hyperplasia
MH  - Male
MH  - Matrix Metalloproteinase 2/analysis
MH  - Matrix Metalloproteinase 9/analysis
MH  - Matrix Metalloproteinase Inhibitors
MH  - Muscle, Smooth, Vascular/chemistry
MH  - Rats
MH  - Tissue Inhibitor of Metalloproteinase-1/*genetics
MH  - Transfection
MH  - Tunica Intima/*pathology
EDAT- 2004/06/15 05:00
MHDA- 2005/01/14 09:00
CRDT- 2004/06/15 05:00
PHST- 2003/07/04 00:00 [received]
PHST- 2004/02/29 00:00 [accepted]
PHST- 2004/06/15 05:00 [pubmed]
PHST- 2005/01/14 09:00 [medline]
PHST- 2004/06/15 05:00 [entrez]
AID - S1525-0016(04)00086-3 [pii]
AID - 10.1016/j.ymthe.2004.02.020 [doi]
PST - ppublish
SO  - Mol Ther. 2004 Jun;9(6):876-84. doi: 10.1016/j.ymthe.2004.02.020.