Transforming Growth Factor‐β:A Promising Target for Anti‐Stenosis Therapy

Chamberlain, Janet

doi:10.1111/j.1527-3466.2001.tb00074.x

Cited by 24 publications

(13 citation statements)

References 142 publications

(155 reference statements)

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“…6 Stent implantation causes a significant increase in collagen synthesis and TGF-␤ expression compared with balloon angioplasty alone. 27,28 In the present study, we demonstrated the abundant collagen deposition associated with TGF-␤1 expression in all layers of stented coronary arteries. TGF-␤ is one of the most potent stimuli for collagen synthesis and may contribute to the formation of restenotic lesions.…”

Section: Mechanism For the Inhibitory Effect Of Fasudil On Neointimalsupporting

confidence: 63%

“…6 Thus, a strategy to inhibit TGF-␤ may be useful in preventing in-stent neointimal formation. 28 In this study, we were able to demonstrate for the first time that long-term treatment with fasudil significantly suppresses collagen deposition in the neointimal lesion after stent implantation due, at least in part, to the inhibition of TGF-␤1 expression.…”

Section: Mechanism For the Inhibitory Effect Of Fasudil On Neointimalmentioning

confidence: 59%

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Long-Term Inhibition of Rho-Kinase Suppresses Neointimal Formation After Stent Implantation in Porcine Coronary Arteries: Involvement of Multiple Mechanisms

Matsumoto

Uwatoku

et al. 2004

ATVB

101

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Objective-We recently demonstrated that Rho-kinase, an effector of the small GTPase Rho, is substantially involved in the pathogenesis of arteriosclerosis. In this study, we examined whether Rho-kinase is also involved in in-stent restenosis and if so, what mechanism is involved. Methods and Results-Pigs underwent stent implantation in the left coronary artery with or without administration of fasudil (30 mg/kg per day orally), a specific Rho-kinase inhibitor, starting 2 days before the procedure for a duration of 4 weeks. On day 28, reductions in coronary diameter and neointimal formation associated with macrophage accumulation, collagen deposition, and transforming growth factor (TGF)-␤1 expression were noted at the stent site, and all were significantly suppressed by fasudil. On day 7, fasudil significantly increased the frequency of TUNEL-positive apoptotic cells, while it tended to reduce that of bromodeoxyuridine-positive proliferating cells in the neointima. Western blot analysis on day 7 demonstrated that phosphorylations of the ezrin/radixin/moesin family (a marker of Rho-kinase activity in vivo) and protein expression of monocyte chemoattractant protein-1and bcl-2 were upregulated at the stent site and were significantly suppressed by fasudil. Conclusions-These results indicate that long-term inhibition of Rho-kinase suppresses in-stent neointimal formation by multiple mechanisms, including reduced vascular inflammation, enhanced apoptosis, and decreased collagen deposition.

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Section: Mechanism For the Inhibitory Effect Of Fasudil On Neointimalsupporting

confidence: 63%

Section: Mechanism For the Inhibitory Effect Of Fasudil On Neointimalmentioning

confidence: 59%

Long-Term Inhibition of Rho-Kinase Suppresses Neointimal Formation After Stent Implantation in Porcine Coronary Arteries: Involvement of Multiple Mechanisms

Matsumoto

Uwatoku

et al. 2004

ATVB

101

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“…Thus, it appears extremely important to fine-tune its activity in vivo (8). Although, manipulating TGF-␤ by inhibiting its expression, activation, or signaling has been used successfully to reduce tissue scarring and fibrosis in some animal models, to date, few of these approaches have reached a clinical trial (50). Given the wideranging interest in developing therapeutics based on targeting TGF-␤, understanding the upstream and downstream mechanisms that regulate its activity is of critical importance.…”

Section: Discussionmentioning

confidence: 99%

IL-13 Activates a Mechanism of Tissue Fibrosis That Is Completely TGF-β Independent

Kaviratne

Hesse

Leusink

et al. 2004

The Journal of Immunology

335

244

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Fibrosis is a characteristic feature in the pathogenesis of a wide spectrum of diseases. Recently, it was suggested that IL-13-dependent fibrosis develops through a TGF-β1 and matrix metalloproteinase-9-dependent (MMP-9) mechanism. However, the significance of this pathway in a natural disorder of fibrosis was not investigated. In this study, we examined the role of TGF-β in IL-13-dependent liver fibrosis caused by Schistosoma mansoni infection. Infected IL-13−/− mice showed an almost complete abrogation of fibrosis despite continued and undiminished production of TGF-β1. Although MMP-9 activity was implicated in the IL-13 pathway, MMP-9−/− mice displayed no reduction in fibrosis, even when chronically infected. To directly test the requirement for TGF-β, studies were also performed with neutralizing anti-TGF-β Abs, soluble antagonists (soluble TGF-βR-Fc), and Tg mice (Smad3−/− and TGF-βRII-Fc Tg) that have disruptions in all or part of the TGF-β signaling cascade. In all cases, fibrosis developed normally and with kinetics similar to wild-type mice. Production of IL-13 was also unaffected. Finally, several genes, including interstitial collagens, several MMPs, and tissue inhibitors of metalloprotease-1 were up-regulated in TGF-β1−/− mice by IL-13, demonstrating that IL-13 activates the fibrogenic machinery directly. Together, these studies provide unequivocal evidence of a pathway of fibrogenesis that is IL-13 dependent but TGF-β1 independent, illustrating the importance of targeting IL-13 directly in the treatment of infection-induced fibrosis.

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“…Lastly, the potential therapeutic application for these endogenous inhibitors of angiogenesis is being considered in the clinic and early results from clinical trials with angiostatin, endostatin, TSP-1 (ABT-510), and 2-ME (Panzam) suggest that more laboratory studies are required to better understand the mechanism of action associated with each of these drug candidates (203)(204)(205)(206)(207)(208)(209). Such continuing efforts will enable us to design more relevant and targeted clinical trial guided by the inherent antiangiogenic mechanism of each particular inhibitor.…”

Section: Summary and Future Perspectivementioning

confidence: 99%