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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:518.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Leukotriene Receptor Antagonism and the Prevention of Extracellular Matrix Degradation During Atherosclerosis and In-Stent Stenosis

Hanna Hlawaty; Marie-Paule Jacob; Liliane Louedec; Didier Letourneur; Charles Brink; Jean-Baptiste Michel; Laurent Feldman; Magnus Bäck

From the INSERM U698 (H.H., M.-P.J., L.L., D.L., C.B., J.-B.M., L.F., M.B.), University of Paris 13 (H.H., D.L.), University of Paris 7 (M.-P.J., C.B., J.-B.M., L.F.), and the Department of Cardiology (L.F., M.B.), Bichat Hospital, Paris, France; and the Center for Molecular Medicine (M.B.), Karolinska University Hospital, Stockholm, Sweden.

Correspondence to Magnus Bäck, MD, PhD, Center for Molecular Medicine, Karolinska University Hospital, L8:03, 17177 Stockholm, Sweden. E-mail Magnus.Back{at}ki.se

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 LTB₄-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 LTB₄.

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.

In the present study, hypercholesteremic rabbits subjected to carotid artery balloon dilatation and stent implantation displayed significantly reduced in-stent intimal hyperplasia after leukotriene receptor antagonist treatment. This effect was in part mediated through reduced MMP activities. The results suggest antileukotrienes as a therapeutic strategy in atherosclerosis and interventional cardiology.

Key Words: lipoxygenase • macrophages • matrix metalloproteinases • restenasis • smooth muscle cells

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