Leukotriene receptor antagonism and the prevention of extracellular matrix degradation during atherosclerosis and in-stent stenosis.
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.


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.
Hlawaty
Hanna
H
INSERM U698, University of Paris, Paris, France.
Jacob
Marie-Paule
MP
Louedec
Liliane
L
Letourneur
Didier
D
Brink
Charles
C
Michel
Jean-Baptiste
JB
Feldman
Laurent
L
Bäck
Magnus
M
D000284:Administration, Oral; D000578:Amidines / Q000008:administration & dosage / Q000494:pharmacology*; D000800:Angioplasty, Balloon / Q000009:adverse effects / Q000295:instrumentation; D000818:Animals; D002219:Carbamates / Q000008:administration & dosage / Q000494:pharmacology*; D017536:Carotid Artery, Common / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016893:Carotid Stenosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D006965:Hyperplasia; D020024:Leukotriene Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008323:Mammary Arteries / Q000378:metabolism / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011817:Rabbits; D055502:Secondary Prevention; D015607:Stents; D013997:Time Factors; D014162:Transfection
D000578:Amidines; D002219:Carbamates; D002791:Cholesterol, Dietary; D020024:Leukotriene Antagonists; D034741:RNA, Small Interfering; D007975:Leukotriene B4; C424425:amelubant; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9