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

Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 29 Số 4 - Trang 518-524 - 2009
Hanna Hlawaty1, Marie‐Paule Jacob1, Liliane Louedec1, Didier Letourneur1, Charles Brink1, Jean‐Baptiste Michel1, Laurent J. Feldman1, Magnus Bäck1
1From 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.

Tóm tắt

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.

Từ khóa


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Thông tin
Thông tin xuất bản

Arteriosclerosis, Thrombosis, and Vascular Biology

Tập 29 Số 4

518-524

Thông tin tác giả