Selective αvβ3 integrin blockade potently limits neointimal hyperplasia and lumen stenosis following deep coronary arterial stent injury1:

Srivatsa, Sanjay S.; Fitzpatrick, Lorraine A.; Tsao, Peter W.; Reilly, Thomas M.; Holmes, David R.; Schwartz, Robert S.; Mousa, Shaker A.

doi:10.1016/s0008-6363(97)00184-3

Cited by 152 publications

(60 citation statements)

References 40 publications

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“…The IC 50 of this peptide for inhibition of 125 I-vitronectin binding to immobilized recombinant ␣V␤3 integrin is 24 nmol/L and 2000 nmol/L for ␣V␤5, 27 and in the range of 0.6 to 4.4 mol/L for ␣V␤3 and Ͼ100 mol/L for ␣5␤1-mediated cell adhesion. 28 The test substance was injected at some distance from the site where the micropuncture needle was inserted, leading to at least a 20-fold dilution of the test substance during its diffusion to the tissue segment in which the P IF was recorded. Thus, the effective concentration of the inhibitor can be calculated to be Ͻ25 mol/L in the present experiments, suggesting that the effect of the inhibitor on P IF is caused by blockage of ␣V␤3 and not ␣5␤1.…”

Section: Resultsmentioning

confidence: 99%

Platelet-Derived Growth Factor BB–Mediated Normalization of Dermal Interstitial Fluid Pressure After Mast Cell Degranulation Depends on β3 but Not β1 Integrins

Lidén

Berg²,

Nedrebø³

et al. 2006

Circulation Research

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Abstract-Interstitial fluid pressure (P IF ) is one of the determinants of transcapillary fluid flux and thereby interstitial fluid volume. Cell-mediated control of P IF regulates fluid content in the loose interstitial connective tissues that surround the capillary bed. To maintain a normal P IF in dermis, ␤1 integrins mediate the tensile strength applied by connective tissue cells on the extracellular matrix. Platelet-derived growth factor (PDGF)-BB normalizes anaphylaxis-induced reduction of P IF . Anti-␤3 integrin IgG and a cyclic RGD peptide that inhibits the ␣V␤3 integrin blocked the ability of PDGF-BB to normalize the lowered P IF resulting from mast cell degranulation. PDGF-BB was unable to normalize P IF lowered as a result of mast cell degranulation in ␤3-negative mice. Monoclonal anti-␤3 integrin IgG had no effect on P IF in normal mouse dermis. In contrast, administration of anti-␤1 integrin IgM lowered P IF in normal dermis but had no effect on PDGF-BB-induced normalization of P IF after anaphylaxis. Furthermore, collagen gel contraction mediated by wild-type mouse embryonal fibroblasts were only marginally affected by function-blocking anti-␤1 integrin antibodies, especially in the presence of PDGF-BB. In contrast, contraction mediated by ␣V-negative mouse embryonic fibroblasts was completely blocked by anti-␤1 integrin antibodies, even after stimulation with PDGF-BB.

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Section: Resultsmentioning

confidence: 99%

Platelet-Derived Growth Factor BB–Mediated Normalization of Dermal Interstitial Fluid Pressure After Mast Cell Degranulation Depends on β3 but Not β1 Integrins

Lidén

Berg²,

Nedrebø³

et al. 2006

Circulation Research

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“…18,19,20 In the present study, we first performed a detailed kinetic analysis in a rat balloon injury model to clarify the essential roles of ␣v␤3 integrin and EC regeneration in neointima formation. Next, we evaluated using in this model the antistenotic effect of BS-1417, a novel ␣v␤3 integrin antagonist.…”

Section: Discussionmentioning

confidence: 99%

A Novel αvβ3 Integrin Antagonist Suppresses Neointima Formation for More Than 4 Weeks After Balloon Injury in Rats

Honda

Kitano

Fukuya

et al. 2005

ATVB

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Objectives-We performed a detailed kinetic analysis in a rat balloon injury model to clarify the essential roles of ␣v␤3 integrin and endothelial cell (EC) regeneration in neointima formation. Using this model, we evaluated the antistenotic effect of Dainippon compound BS-1417, a novel ␣v␤3 integrin antagonist. Methods and Results-Kinetic analysis using RT-PCR showed that ␣v␤3 integrin-related genes are upregulated before neointima formation. Morphological and functional analyses revealed that EC regeneration requires Ͼ4 weeks after injury, and that recovery of EC normal function coincides with the arrest of neointima formation. Subcutaneous infusion of BS-1417 for 2, 4, 7, or 12 weeks after injury potently inhibited neointima formation without affecting EC regeneration. Although withdrawal of treatment with BS-1417 after short-term administration after injury resulted in catch-up growth of neointima, a long-term study suggested that this catch-up growth can be prevented by continuous administration of BS-1417 until EC regeneration. Conclusion-We clarified that ␣v␤3 integrin and EC regeneration play an essential role in neointima formation, and that continuous administration of BS-1417 potently and stably inhibits neointima formation without affecting EC regeneration. These findings suggest that BS-1417 might be useful as a novel systemic drug for the treatment of restenosis. 3,4 It is also known that regeneration of endothelial cells (ECs) plays an important role in preventing SMC proliferation. 5,6 Given systemically, numerous single molecule drugs for the prevention of neointima formation in animal models have been reported. 7 However, these drugs have shown only short-term efficacy in animal models 7 and no promising result in clinical trials. 7,8 See page 1309 ␣v␤3 integrin, also called vitronectin receptor, is expressed on a variety of cell types, 9 including SMCs and ECs, and it is known to mediate migration or proliferation of certain cells in disease states, including SMCs in restenosis after vascular injury, 10 and ECs and SMCs in angiogenesis. 11 Although many cyclic peptide and nonpeptide ␣v␤3 integrin antagonists have been reported, 12,13 only a few have been shown to potently inhibit neointima formation in rat models.In preliminary in vitro studies aimed at finding selective inhibitors of SMC proliferation, we found a series of ␣v␤3 integrin antagonists that inhibit SMC proliferation without affecting EC proliferation. Based on this finding and the results of a previous study showing that small-molecule ␣v␤3 integrin antagonists effectively inhibit neointima formation in rats, 14 we focused our efforts on ␣v␤3 integrin antagonists and recently found a new series of promising phenylpiperazine-based ␣v␤3 integrin antagonists. 15 Extensive screening of these novel antagonists using a rat balloon injury model led us to the discovery of BS-1417 ( Figure I, available online at http://atvb.ahajournals.org) as a suitable candidate for further development. 15 In the present study, we first performed a deta...

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“…In vitro assays specific for adhesion mediated by ␣ v ␤ 3 (rabbit SMC/fibrinogen), ␣ IIb ␤ 3 (rabbit platelet aggregation), ␣ v ␤ 5 (rabbit SMC to vitronectin), and ␣ 5 ␤ 1 (rabbit SMC to biotinylated fibronectin) were performed by methods described previously. 11,12 All results are reported as the concentration required to inhibit 50% binding (IC 50 ) and are the mean of 3 experiments.…”

Section: ␣ V ␤ 3 -Integrin Receptor Antagonistmentioning

confidence: 99%

“…Our findings extend the observations of others in nonatherosclerotic animals. 1,7,12 However, the arterial response to injury may be quite different in atherosclerotic versus nonatherosclerotic arteries secondary to differences in vascular wall composition (ie, lipid, inflammatory cell, and extracellular matrix) at the time of injury. 9 In some nonatherosclerotic animal studies, 1,2 but not all, 7 ␣ v ␤ 3 -receptor inhibition at the time of balloon injury was thought to limit the arterial response to injury by inhibiting SMC migration.…”

Section: Bishop Et Al ␣ V ␤ 3 -Receptor Blockade Reduces Restenosis 1909mentioning

confidence: 99%

Selective α _v β ₃ -Receptor Blockade Reduces Macrophage Infiltration and Restenosis After Balloon Angioplasty in the Atherosclerotic Rabbit

et al. 2001

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Background-␣ v ␤ 3 -Integrin receptors are upregulated in atherosclerotic arteries and play a key role in smooth muscle cell and possibly inflammatory cell migration. We hypothesized that after balloon angioplasty (BA) of atherosclerotic arteries, selective inhibition of the ␣ v ␤ 3 -receptor by XT199, a small-molecule, non-peptide-selective ␣ v ␤ 3 -receptor antagonist, would reduce restenosis. Methods and Results-After induction of focal atherosclerosis, rabbits underwent femoral BA and received XT199 (2.5 mg/kg IV bolus plus 2.5 mg

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Selective αvβ3 integrin blockade potently limits neointimal hyperplasia and lumen stenosis following deep coronary arterial stent injury1:

Cited by 152 publications

References 40 publications

Platelet-Derived Growth Factor BB–Mediated Normalization of Dermal Interstitial Fluid Pressure After Mast Cell Degranulation Depends on β3 but Not β1 Integrins

Platelet-Derived Growth Factor BB–Mediated Normalization of Dermal Interstitial Fluid Pressure After Mast Cell Degranulation Depends on β3 but Not β1 Integrins

A Novel αvβ3 Integrin Antagonist Suppresses Neointima Formation for More Than 4 Weeks After Balloon Injury in Rats

Selective α _v β ₃ -Receptor Blockade Reduces Macrophage Infiltration and Restenosis After Balloon Angioplasty in the Atherosclerotic Rabbit

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Selective αvβ3 integrin blockade potently limits neointimal hyperplasia and lumen stenosis following deep coronary arterial stent injury1:

Cited by 152 publications

References 40 publications

Platelet-Derived Growth Factor BB–Mediated Normalization of Dermal Interstitial Fluid Pressure After Mast Cell Degranulation Depends on β3 but Not β1 Integrins

Platelet-Derived Growth Factor BB–Mediated Normalization of Dermal Interstitial Fluid Pressure After Mast Cell Degranulation Depends on β3 but Not β1 Integrins

A Novel αvβ3 Integrin Antagonist Suppresses Neointima Formation for More Than 4 Weeks After Balloon Injury in Rats

Selective α v β 3 -Receptor Blockade Reduces Macrophage Infiltration and Restenosis After Balloon Angioplasty in the Atherosclerotic Rabbit

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Selective α _v β ₃ -Receptor Blockade Reduces Macrophage Infiltration and Restenosis After Balloon Angioplasty in the Atherosclerotic Rabbit