Tranilast suppresses the vascular intimal hyperplasia after balloon injury in rabbits fed on a high-cholesterol diet

Fukuyama, Juichi; Ichikawa, Kazuhiko; Hamano, Shuichiro; Shibata, Nobuhiko

doi:10.1016/s0014-2999(96)00774-1

Cited by 34 publications

(19 citation statements)

References 20 publications

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“…38,39 However, this compound has been shown the antiproliferative and antiinflammatory actions in other cell types, such as vascular smooth muscle cells and neutrophils. 40,41 We demonstrated the specific action of …”

Section: Discussionmentioning

confidence: 89%

Adventitial Mast Cells Contribute to Pathogenesis in the Progression of Abdominal Aortic Aneurysm

Tsuruda

Kato²,

Hatakeyama³

et al. 2008

Circulation Research

148

147

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Abstract-Abdominal aortic aneurysm (AAA) is histologically characterized by medial degeneration and various degrees of chronic adventitial inflammation, although the mechanisms for progression of aneurysm are poorly understood. In the present study, we carried out histological study of AAA tissues of patients, and interventional animal and cell culture experiments to investigate a role of mast cells in the pathogenesis of AAA. The number of mast cells was found to increase in the outer media or adventitia of human AAA, showing a positive correlation between the cell number and the AAA diameter. Aneurysmal dilatation of the aorta was seen in the control (ϩ/ϩ) rats following periaortic application of calcium chloride (CaCl 2 ) treatment but not in the mast cell-deficient mutant Ws/Ws rats. The AAA formation was accompanied by accumulation of mast cells, T lymphocytes and by activated matrix metalloproteinase 9, reduced elastin levels and augmented angiogenesis in the aortic tissue, but these changes were much less in the Ws/Ws rats than in the controls. Similarly, mast cells were accumulated and activated at the adventitia of aneurysmal aorta in the apolipoprotein E-deficient mice. The pharmacological intervention with the tranilast, an inhibitor of mast cell degranulation, attenuated AAA development in these rodent models. In the cell culture experiment, a mast cell directly augmented matrix metalloproteinase 9 activity produced by the monocyte/macrophage. Collectively, these data suggest that adventitial mast cells play a critical role in the progression of AAA. Key Words: adventitia Ⅲ inflammation Ⅲ mast cell Ⅲ matrix metalloproteinase Ⅲ aneurysm A bdominal aortic aneurysm (AAA), a relatively common disorder among elderly people, is pathologically characterized by atherosclerosis of the intima and disruption or attenuation of the elastic media with various degrees of adventitial inflammatory infiltration. 1,2 Because approximately 4% of adults older than 65 years harbor AAA, it is among the leading 15 causes of death in elderly persons in the United States. 3 Although substantial efforts have been made to clarify the mechanism of development of AAA, there is currently no effective method to inhibit enlargement of AAA. Repair surgery is necessary to prevent rupture in patients with progressively enlarging AAA, whereas the operative risk is often relatively high because of the other complications resulting from aging.Recent reports suggest that chronic inflammation of the aortic wall and progressive degradation of extracellular matrix proteins are involved in the development, progression, or rupture of AAA. 2,4 -8 As a component of the immune system, mast cells play a critical role in defending hosts against pathogens by releasing a number of immunoregulatory mediators. 9 These cells have also been shown to initiate the inflammatory response by releasing proinflammatory cytokines, growth factors, angiogenic mediators, and proteases, 10 as well as by recruiting other inflammatory cells, such as neutrophils, macrop...

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Section: Discussionmentioning

confidence: 89%

Adventitial Mast Cells Contribute to Pathogenesis in the Progression of Abdominal Aortic Aneurysm

Tsuruda

Kato²,

Hatakeyama³

et al. 2008

Circulation Research

148

147

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“…This antiproliferative action has been investigated in several animal models of arterial injury for the prevention of vascular intimal thickening. [32][33][34][35][36] p21 Waf1/Cip1 has been reported to play an important regulatory role in the control of cell proliferation. It is an intrinsic inhibitor of cyclin/cyclin-dependent kinase complexes [12][13][14][15] and can limit cell progression through G 1 to S phase.…”

Section: Izawa Et Al Tranilast Inhibits Cardiac Allograft Vasculopathymentioning

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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“…It has been shown to effectively inhibit lesion formation after vascular injury in rabbits fed a high-cholesterol diet. 8 Tranilast has been shown to interfere with the migration of vascular smooth muscle cells (VSMCs), a component of postangioplasty restenosis, in vitro. 9 Recently, it has been reported that tranilast inhibits VSMC proliferation, another component of restenosis, and that this activity is correlated with upregulation of the cyclin-dependent kinase (Cdk) inhibitor p21 WAF1 (p21) in vitro and in vivo.…”

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confidence: 99%

Mouse Genetic Evidence That Tranilast Reduces Smooth Muscle Cell Hyperplasia via a p21 ^WAF1 -Dependent Pathway

Sata

Takahashi²,

Tanaka³

et al. 2002

ATVB

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Objective-N-(3Ј4Ј-dimethoxycinnamoyl)-anthranilic acid (tranilast) is a drug that has been shown to reduce the incidence of restenosis after angioplasty in middle-scale clinical trials. Despite clinical interest in this drug, the pharmacological actions of tranilast remain relatively unexplored at a molecular level. Methods and Results-We evaluated the effects of tranilast on vascular smooth muscle cell (VSMC) proliferation in wild-type mice and in mice lacking a cyclin-dependent kinase inhibitor, p21 WAF1 (p21). Tranilast potently inhibited the proliferation of VSMC cultures derived from wild-type mice, but VSMCs derived from p21-deficient (p21Ϫ/Ϫ) mice were unaffected by this treatment. In a mouse femoral artery model of vascular injury, tranilast administration to wild-type mice led to an upregulation of p21 expression and a decrease in the number of proliferating VSMCs, as determined by immunostaining for proliferating cell nuclear antigen. In contrast, tranilast had no effect on the number of proliferating cell nuclear antigen-positive cells in the injured arteries of p21Ϫ/Ϫ mice. Administration of tranilast significantly reduced the neointimal VSMC hyperplasia in wild-type mice at 4 weeks but had no effect on lesion formation in p21Ϫ/Ϫ mice. Conclusions-Our findings provide genetic evidence that tranilast inhibits intimal hyperplasia via a p21-dependent pathway, an activity that may contribute to its efficacy in the prophylactic treatment of postangioplasty restenosis. Key Words: pharmacology Ⅲ genetically altered mice Ⅲ smooth muscle cells Ⅲ restenosis Ⅲ proliferation P ercutaneous transluminal angioplasty has been widely adopted as a treatment of atherosclerosis. However, in a significant number of cases, the procedure fails because of postangioplasty restenosis. 1 Although the increasing use of new devices to dilate stenosed arteries has lowered the incidence of acute complications, restenosis still limits the long-term outcome of percutaneous interventions. 2 Although much effort has been devoted to the development of strategies to prevent postangioplasty restenosis, 3 as yet, no pharmacological treatment has been approved to reduce postangioplasty restenosis.N-(3Ј4Ј-Dimethoxycinnamoyl)-anthranilic acid (tranilast) is a drug that may be effective in preventing angiographic restenosis after percutaneous transluminal coronary revascularization, inasmuch as the results of middle-scale, randomized, double-blind, placebo-controlled trials have shown that oral administration of tranilast significantly lowers the incidence of restenosis after conventional balloon angioplasty, 4 directional coronary atherectomy, 5 and coronary stenting. 6 A multicenter, phase-3, double-blind, placebo-controlled trial is currently under way to evaluate the effects of tranilast on clinical, angiographic, and intravascular ultrasound findings of restenosis. 7 Despite the clinical interest in this drug, the pharmacological actions of tranilast remain relatively unexplored, particularly regarding its action in the vasculature. It h...

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Tranilast suppresses the vascular intimal hyperplasia after balloon injury in rabbits fed on a high-cholesterol diet

Cited by 34 publications

References 20 publications

Adventitial Mast Cells Contribute to Pathogenesis in the Progression of Abdominal Aortic Aneurysm

Adventitial Mast Cells Contribute to Pathogenesis in the Progression of Abdominal Aortic Aneurysm

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

Mouse Genetic Evidence That Tranilast Reduces Smooth Muscle Cell Hyperplasia via a p21 ^WAF1 -Dependent Pathway

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Tranilast suppresses the vascular intimal hyperplasia after balloon injury in rabbits fed on a high-cholesterol diet

Cited by 34 publications

References 20 publications

Adventitial Mast Cells Contribute to Pathogenesis in the Progression of Abdominal Aortic Aneurysm

Adventitial Mast Cells Contribute to Pathogenesis in the Progression of Abdominal Aortic Aneurysm

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

Mouse Genetic Evidence That Tranilast Reduces Smooth Muscle Cell Hyperplasia via a p21 WAF1 -Dependent Pathway

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Product

Resources

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

Mouse Genetic Evidence That Tranilast Reduces Smooth Muscle Cell Hyperplasia via a p21 ^WAF1 -Dependent Pathway