Abstract
Objective:
The lipid-derived inflammatory mediators leukotrienes (LTs) are produced during vascular injury. The aim of the present study was to determine the role of LT receptor signaling in the pathophysiology of in-stent stenosis.
Methods and results:
New Zealand White rabbits were fed 0.3% cholesterol and subjected to angioplasty with balloon dilatation and stent implantation in the right carotid artery. Rabbits treated for 2 weeks with the BLT receptor antagonist BIIL284 (3 mg/kg once daily by oral gavage) displayed a significantly reduced in-stent intimal hyperplasia in carotid arteries compared with vehicle-treated rabbits. In addition, BIIL284 treatment significantly reduced the extracellular matrix metalloproteinase (MMP)-2 and MMP-9 activities in stented arteries. The inhibited MMP-9 activity was correlated with decreased macrophage content in the lesions. The LTB(4)-induced migration of vascular smooth muscle cells was significantly inhibited by transfection with siRNA against MMP-2. Finally, human arteries subjected to ex vivo angioplasty and stent implantation displayed an increased in-stent intimal hyperplasia and higher MMP-2 and -9 activities in the presence of LTB(4).
Conclusions:
These results suggest a key role of LT signaling in the extracellular matrix degradation associated with hyperlipidemia and in-stent stenosis. In conclusion, targeting LT receptors may represent a therapeutic strategy in atherosclerosis and interventional cardiology.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Amidines / administration & dosage
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Amidines / pharmacology*
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Angioplasty, Balloon* / adverse effects
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Angioplasty, Balloon* / instrumentation
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Animals
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Carbamates / administration & dosage
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Carbamates / pharmacology*
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Carotid Artery, Common / drug effects*
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Carotid Artery, Common / metabolism
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Carotid Artery, Common / pathology
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Carotid Stenosis / etiology
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Carotid Stenosis / metabolism
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Carotid Stenosis / pathology
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Carotid Stenosis / therapy*
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Cell Line
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Cholesterol, Dietary / administration & dosage
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Disease Models, Animal
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Extracellular Matrix / metabolism*
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Humans
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Hyperplasia
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Leukotriene Antagonists / administration & dosage
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Leukotriene Antagonists / pharmacology*
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Leukotriene B4 / metabolism*
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Macrophages / drug effects
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Macrophages / metabolism
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Male
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Mammary Arteries / metabolism
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Mammary Arteries / pathology
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Matrix Metalloproteinase 2 / metabolism
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Matrix Metalloproteinase 9 / metabolism
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Muscle, Smooth, Vascular / drug effects
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Muscle, Smooth, Vascular / metabolism
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Myocytes, Smooth Muscle / drug effects
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Myocytes, Smooth Muscle / metabolism
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Organ Culture Techniques
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RNA Interference
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RNA, Small Interfering / metabolism
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Rabbits
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Secondary Prevention
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Stents*
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Time Factors
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Transfection
Substances
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Amidines
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Carbamates
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Cholesterol, Dietary
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Leukotriene Antagonists
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RNA, Small Interfering
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Leukotriene B4
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amelubant
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Matrix Metalloproteinase 2
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Matrix Metalloproteinase 9