Adenovirus-Mediated Gene Transfer of the Human TIMP-1 Gene Inhibits Smooth Muscle Cell Migration and Neointimal Formation in Human Saphenous Vein

George, Sarah J.; Johnson, Jason L.; Angelini, Gianni D; Newby, AC; Baker, Andrew H.

doi:10.1089/hum.1998.9.6-867

Cited by 193 publications

(125 citation statements)

References 37 publications

(29 reference statements)

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“…Given the lack of effects on MMP expression and activation, inhibition of active MMPs appears to be the main factor underlying the inhibition of SMC migration by TIMP-2 overexpression. Data showing that TIMP-1 overexpression 12 and a nonselective synthetic MMP inhibitor, Ro 31-9790, also reduce neointimal thickening to a similar extent in HSV organ cultures 8 are consistent with this conclusion.…”

Section: Figure 5 Effect Of Radtimp-2 Infection On Neointima Formatiosupporting

confidence: 55%

“…12 TIMP-1 overexpression inhibited SMC migration and neointima formation while an adenovirus expressing ␤-galactosidase had no significant effect. The potential for using other TIMP genes for gene therapy has not, however, been investigated.…”

Section: Correspondence: Ah Bakermentioning

confidence: 94%

“…12 Given this localised infection, it is all the more remarkable that total levels of TIMP-2 secretion were elevated as shown by reverse zymography. This is undoubtedly due to the high efficiency of transgene transcription from the CMV IEP in HSV organ cultures.…”

Section: Figure 5 Effect Of Radtimp-2 Infection On Neointima Formatiomentioning

confidence: 94%

“…The adventitia was removed, the vein bisected transversely and one segment used as a paired uninfected control. The vein was infused with 100 l of 1.2 × 10 10 p.f.u./ml RAd-TIMP-2 as described previously 12 for a period of 1 h. Segments were then opened longitudinally and cut transversely into three 5-10-mm segments. The uninfected control was cut similarly.…”

Section: Infection Of Human Saphenous Veinmentioning

confidence: 99%

“…7,12 Briefly, sections were washed twice in 1 × TE (10 mm Tris HCl pH 8.0, 1 mm EDTA) and incubated in labelling mix (50 mm Tris HCl (pH 7.2), 10 mm MgSO 4 , 0.1 mm dithiothreitol, 0.01 mm dATP, dCTP, dGTP, 0.01 mm biotin-dUTP, and 8 units/ml of DNA polymerase I (Klenow; Promega, Southampton, UK) for 15 min at room temperature. Sections were rinsed in 1 × TE and endogenous peroxidase inhibited by incubation in 2% H 2 O 2 for 5 min.…”

Section: Determination Of Cell Viabilitymentioning

confidence: 99%

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Gene transfer of tissue inhibitor of metalloproteinase-2 inhibits metalloproteinase activity and neointima formation in human saphenous veins

et al. 1998

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Metalloproteinases (MMPs) are implicated in neointima for-21.8 ± 2.9 ng/mg wet weight/day (P Ͻ 0.05, n = 3). In situ mation and hence vein graft failure. Gene transfer to elevzymography revealed a marked inhibition of gelatinolytic ate local levels of tissue inhibitor of metalloproteinases activity by TIMP-2 gene transfer throughout the vein seg-(TIMPs) is therefore a potential treatment. In this study, we ments. Neointima formation and neointimal cell numbers have used lumenal application of a replication-defective were reduced 79% and 71%, respectively (P Ͻ 0.05; recombinant adenovirus to overexpress TIMP-2 and n = 8). TIMP-2 overexpression had no effect on smooth observe the effects on neointimal thickening in a well muscle cell proliferation, secretion of pro-MMP-2 or -9 and characterised human saphenous vein organ culture model.did not inhibit the processing of pro-MMP-2 to its active Increased TIMP-2 expression was localised to lumenal form. Our data indicate that TIMP-2 overexpression surface cells but nevertheless increased total functional reduces neointimal thickening, primarily by inhibiting MMP TIMP-2 secretion after 14 days culture from 4.0 ± 2.0 to activity and hence smooth muscle cell migration.

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Section: Figure 5 Effect Of Radtimp-2 Infection On Neointima Formatiosupporting

confidence: 55%

Section: Correspondence: Ah Bakermentioning

confidence: 94%

Section: Figure 5 Effect Of Radtimp-2 Infection On Neointima Formatiomentioning

confidence: 94%

Section: Infection Of Human Saphenous Veinmentioning

confidence: 99%

Section: Determination Of Cell Viabilitymentioning

confidence: 99%

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Gene transfer of tissue inhibitor of metalloproteinase-2 inhibits metalloproteinase activity and neointima formation in human saphenous veins

et al. 1998

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Molecular mechanisms in intimal hyperplasia

2000

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Intimal hyperplasia is the process by which the cell population increases within the innermost layer of the arterial wall, such as occurs physiologically during closure of the ductus arteriosus and during involution of the uterus. It also occurs pathologically in pulmonary hypertension, atherosclerosis, after angioplasty, in transplanted organs, and in vein grafts. The underlying causes of intimal hyperplasia are migration and proliferation of vascular smooth muscle cells provoked by injury, inflammation, and stretch. This review discusses, at a molecular level, both the final common pathways leading to smooth muscle migration and proliferation and their (patho)‐physiological triggers. It emphasizes the key roles played by growth factors and extracellular matrix‐degrading metalloproteinases, which act in concert to remodel the extracellular matrix and permit cell migration and proliferation. Copyright © 2000 John Wiley & Sons, Ltd.

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Paradoxical effects of tissue inhibitor of metalloproteinases 1 gene transfer in collagen-induced arthritis

Apparailly¹,

Noël²,

Millet³

et al. 2001

Arthritis & Rheumatism

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Objective The imbalance between matrix metalloproteinases (MMPs) 1, 3, and 9 and their specific inhibitor, tissue inhibitor of metalloproteinases 1 (TIMP‐1), is a critical step in cartilage injury and angiogenesis in arthritis. To explore the therapeutic potential of TIMP‐1 gene transfer in erosive arthritis, the effects of an adenoviral vector (Ad‐TIMP‐1) were assessed in DBA/1 mice with collagen‐induced arthritis (CIA). Methods DBA/1 mice with CIA received an intravenous injection of replication‐deficient adenovirus containing the human TIMP‐1 gene or a control LacZ gene on day 28 postimmunization. The efficiency of gene transfer was determined by serum TIMP‐1 detection, measurements of paw swelling, as well as radiologic and histologic examination of the paws. Results A single administration of Ad‐TIMP‐1 resulted in detectable serum levels of the exogenous protein for at least 13 days. The incidence and onset of arthritis were not statistically modified after human TIMP‐1 gene transfer in DBA/1 mice compared with control mice. However, the severity of inflammation was statistically significantly increased in Ad‐TIMP‐1–treated mice and a similar trend was observed in the histologic and radiologic scores. With regard to the mechanisms of the worsened effect in the Ad‐TIMP‐1–treated mice, we observed 1) higher serum levels of anti–type II collagen IgG2a, 2) a significant increase in endogenous soluble tumor necrosis factor receptor I (TNFRI) in sera, and 3) increased labeling of mouse tumor necrosis factor α and TNFRI within arthritic joints. Conclusion These findings show that overexpression of TIMP‐1 does not prevent osteochondral injury in a mouse model of arthritis. Since MMPs have overlapping properties in terms of their roles in extracellular matrix degradation, angiogenesis, and shedding of cell surface adhesion molecules, cytokines, and cytokine receptors, the paradoxical results obtained suggest that TIMP‐1 is probably not the main inhibitor to target.

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Adenovirus-Mediated Gene Transfer of the Human TIMP-1 Gene Inhibits Smooth Muscle Cell Migration and Neointimal Formation in Human Saphenous Vein

Cited by 193 publications

References 37 publications

Gene transfer of tissue inhibitor of metalloproteinase-2 inhibits metalloproteinase activity and neointima formation in human saphenous veins

Gene transfer of tissue inhibitor of metalloproteinase-2 inhibits metalloproteinase activity and neointima formation in human saphenous veins

Molecular mechanisms in intimal hyperplasia

Paradoxical effects of tissue inhibitor of metalloproteinases 1 gene transfer in collagen-induced arthritis

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