Effectiveness of tranilast on restenosis after directional coronary atherectomy

Kosuga, Kunihiko; Tamai, Hideo; Ueda, Kinzo; Hsu, Yung-Sheng; Ono, Shinji; Tanaka, Shōzō; Doi, Tôru; Myou-U, Wang; Motohara, Seiichiro; Uehata, Hiromu

doi:10.1016/s0002-8703(97)70055-3

Cited by 62 publications

(31 citation statements)

References 21 publications

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“…83 In addition, since many tumors express increased amounts of TGF-β, agents that block TGF-β may be valuable in stimulating an immune response toward metastases. 84 Mechanisms to block TGF-β activity include soluble TβRII fragments, 85 decorin, 86 tranilast, 87 neutralizing antibodies, 88 threonine kinase inhibitors, 89 and RNA expression inhibitors such as anti-sense expression vectors or blocking oligonucleotides. 90 Impressive results have been obtained in animal models of fibrosis using TGF-β antagonists.…”

Section: Antagonists Of Tgf-β For Disease Treatmentmentioning

confidence: 99%

Medical Applications of Transforming Growth Factor-

Flanders¹,

Burmester²

2003

Clinical Medicine & Research

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Transforming growth factor-β (TGF-β) proteins and their antagonists have entered clinical trials. These multi-functional regulators of cell growth and differentiation induce extracellular matrix proteins and suppress the immune system making TGF-βs useful in treatment of wounds with impaired healing, mucositis, fractures, ischemia-reperfusion injuries, and autoimmune disease. In diseases such as keloids, glomerulonephritis and pulmonary fibrosis, excessive expression of TGF-β has been implicated as being responsible for accumulation of detrimental scar tissue. In these conditions, agents that block TGF-β have prevented or reversed disease. Similarly, in carcinogenesis, blocking TGF-β activity may be valuable in stimulating an immune response towards metastasis. As these blocking agents receive approval, we will likely have new therapies for previously recalcitrant diseases.

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Section: Antagonists Of Tgf-β For Disease Treatmentmentioning

confidence: 99%

Medical Applications of Transforming Growth Factor-

Flanders¹,

Burmester²

2003

Clinical Medicine & Research

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“…Several recent clinical trials have shown the potent effect of tranilast in preventing restenosis after percutaneous transluminal coronary angioplasty (PTCA) 8 and after directional coronary atherectomy. 9 A further double-blind placebo-controlled multicenter trial is now testing whether tranilast can prevent restenosis after percutaneous transluminal coronary revascularization with or without stenting for single or multiple vessels. 10 This agent inhibits collagen synthesis as well as migration and proliferation of cultured vascular smooth muscle cells.…”

mentioning

confidence: 99%

Tranilast Inhibits Cardiac Allograft Vasculopathy in Association With p21 ^Waf1/Cip1 Expression on Neointimal Cells in Murine Cardiac Transplantation Model

Izawa

Suzuki²,

Takahashi³

et al. 2001

ATVB

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Abstract-Cardiac allograft vasculopathy is a major complication after cardiac transplantation, often limiting long-term recipient survival. N- (3,anthranilic acid (tranilast) inhibits cyclin-dependent kinase activity through p21 Waf1/Cip1 induction and arrests vascular smooth muscle cell proliferation in vitro. We tested a hypothesis that tranilast inhibits the vasculopathy characterized by diffuse intimal thickening in a murine heart transplantation model. Hearts from DBA/2 mice were heterotopically transplanted into B10.D2 mice as allografts. Oral administration of tranilast started 3 days before transplantation at doses of 550 or 1040 mg/kg per day until the animals were killed. Cardiac allograft vasculopathy was defined as luminal stenosis caused by neointimal formation. The percentage of luminal stenosis and cardiac rejection were analyzed 14 and 28 days after transplantation. Tranilast administration was associated with a marked reduction in luminal occlusion but with no significant effect on cardiac rejection. Immunohistochemical study of the tranilast-treated graft coronary arteries revealed enhancement of p21Waf1/Cip1 and decreased expression of proliferating cell nuclear antigen in the neointima. The significant reduction in allograft vasculopathy concomitant with the enhancement of p21Waf1/Cip1 indicates that tranilast has an antiproliferative effect that could be applicable to clinical treatment of cardiac allograft vasculopathy.

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“…17,18 This compound is now gaining interest in human cardiovascular disease as a possible therapy for restenosis. 19 The hypothesis we sought to test is that in the hypertensive Ren2 rat, the increased angiotensin II level, independent of its hypertensive effect, augments left ventricular TGF␤ 1 expression and thereby increases collagen content, which leads to impaired left ventricular performance and decreased survival. Therefore, we also assessed the effects of tranilast in direct comparison with a nonhypotensive dose of losartan, a specific angiotensin II type 1 (AT 1 ) receptor antagonist.…”

mentioning

confidence: 99%

Reduction in Left Ventricular Messenger RNA for Transforming Growth Factor β ₁ Attenuates Left Ventricular Fibrosis and Improves Survival Without Lowering Blood Pressure in the Hypertensive TGR(mRen2)27 Rat

et al. 2000

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Abstract-Angiotensin II recruits transforming growth factor ␤ 1 (TGF␤ 1 ) and is related to left ventricular fibrosis.However, it is unclear whether chronic in vivo reduction in left ventricular TGF␤ 1 expression blunts fibrosis and improves outcome in angiotensin II-dependent hypertension. Four-week-old male hypertensive TGR(mRen2)27 (Ren2) rats received either normal food, low-dose losartan (0.5 mg ⅐ kg) (nϭ10 for each group) for 12 weeks and were compared with Sprague-Dawley control rats. The effect of tranilast on survival was evaluated in 34 additional untreated homozygous Ren2 rats. Tranilast or low-dose losartan did not lower blood pressure. However, the increase in left ventricular weight (Ren2 versus SD 3.1Ϯ0.16 versus 2.1Ϯ 0.06 mg/g body wt; PϽ0.05) was significantly (PϽ0.05) blunted by both tranilast (2.7Ϯ0.05) and losartan (2.7Ϯ0.07). Both drugs prevented the increase in left ventricular TGF␤ 1 mRNA and fibronectin mRNA and blunted the increase in hydroxyproline content and the increase in perivascular fibrosis. The perivascular fibrosis score correlated significantly with the level of expression of TGF␤ 1 (rϭ0.62; Pϭ0.019). In situ hybridization demonstrated increases in TGF␤ 1 mRNA, predominantly in perivascular and nonmyocyte areas. Both drugs did not prevent the decrease in systolic or diastolic dP/dt, but tranilast significantly improved the survival of untreated Ren2 rats (Pϭ0.029). In conclusion, TGF␤ 1 mRNA expression is increased predominantly in nonmyocyte regions in the hypertrophied left ventricle in this angiotensin II-dependent model of hypertension. This increase is probably due to high angiotensin II levels rather than to hypertension. This is the first study to suggest that chronic inhibition of TGF␤ 1 expression attenuates left ventricular hypertrophy and fibrosis, even without lowering blood pressure. (Hypertension. 2000;36:747-754.) Key Words: hypertension, experimental Ⅲ hypertrophy Ⅲ transforming growth factors Ⅲ fibrosis H ypertension-related left ventricular hypertrophy is associated with an adverse outcome, 1 although hypertrophy is a normal adaptation to increased loading and is invariably found in every rat model of hypertension. 2 This suggests that only part of the hypertrophic process is maladaptive. It is thought that this maladaptive part of cardiac hypertrophy is related to increased expression of growth factors in the heart, which eventually lead to excess fibrosis. Consequently, it has been proposed that a reduction in growth factors could prevent such adverse changes. 3 A central role in this process has been proposed for transforming growth factor ␤ 1 (TGF␤ 1 ). Although all 3 isoforms of TGF␤ (TGF␤ 1 , -␤ 2 , and -␤ 3 ) are present in the heart, the level of the type 1 isoform seems to be particularly related to the development of left ventricular hypertrophy. 4 TGF␤ 1 is secreted by most cell types and has complex actions, depending on the cell type that is involved: it inhibits the proliferation of many cells but also stimulates the growth of mesenchymal cells ...

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Effectiveness of tranilast on restenosis after directional coronary atherectomy

Cited by 62 publications

References 21 publications

Medical Applications of Transforming Growth Factor-

Medical Applications of Transforming Growth Factor-

Tranilast Inhibits Cardiac Allograft Vasculopathy in Association With p21 ^Waf1/Cip1 Expression on Neointimal Cells in Murine Cardiac Transplantation Model

Reduction in Left Ventricular Messenger RNA for Transforming Growth Factor β ₁ Attenuates Left Ventricular Fibrosis and Improves Survival Without Lowering Blood Pressure in the Hypertensive TGR(mRen2)27 Rat

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Effectiveness of tranilast on restenosis after directional coronary atherectomy

Cited by 62 publications

References 21 publications

Medical Applications of Transforming Growth Factor-

Medical Applications of Transforming Growth Factor-

Tranilast Inhibits Cardiac Allograft Vasculopathy in Association With p21 Waf1/Cip1 Expression on Neointimal Cells in Murine Cardiac Transplantation Model

Reduction in Left Ventricular Messenger RNA for Transforming Growth Factor β 1 Attenuates Left Ventricular Fibrosis and Improves Survival Without Lowering Blood Pressure in the Hypertensive TGR(mRen2)27 Rat

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Tranilast Inhibits Cardiac Allograft Vasculopathy in Association With p21 ^Waf1/Cip1 Expression on Neointimal Cells in Murine Cardiac Transplantation Model

Reduction in Left Ventricular Messenger RNA for Transforming Growth Factor β ₁ Attenuates Left Ventricular Fibrosis and Improves Survival Without Lowering Blood Pressure in the Hypertensive TGR(mRen2)27 Rat