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Am J Physiol Heart Circ Physiol 293: H3593-H3601, 2007. First published September 21, 2007; doi:10.1152/ajpheart.00517.2007
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Inhibition of MMP-2 gene expression with small interfering RNA in rabbit vascular smooth muscle cells

Hanna Hlawaty,1,2 Aurélie San Juan,1,2 Marie-Paule Jacob,1,2 Roger Vranckx,1,2 Didier Letourneur,1,2 and Laurent J. Feldman1,2,3

1Institut National de la Santé et de la Recherche Médicale, U698, Université Paris 7, Paris, F75018; 2Institut Galilée, Université Paris 13, Villetaneuse, 93430; and 3Département de Cardiologie, Assistance Publique-Hôpitaux de Paris, Hôpital X. Bichat, Paris, France

Submitted 20 April 2007 ; accepted in final form 17 September 2007

Matrix metalloproteinase-2 (MMP-2) is constitutively expressed in vascular smooth muscle cells (VSMCs). Using small interfering RNA (siRNA), we evaluated the effect of MMP-2 inhibition in VSMCs in vitro and ex vivo. Rabbit VSMCs were transfected in vitro with 50 nmol/l MMP-2 siRNA or scramble siRNA. Flow cytometry and confocal microscopy showed cellular uptake of siRNA in ~80% of VSMCs. MMP-2 mRNA levels evaluated by real-time RT-PCR, pro-MMP-2 activity from conditioned culture media evaluated by gelatin zymography, and VSMC migration were reduced by 44 ± 19%, 43 ± 14%, and 36 ± 14%, respectively, in MMP-2 siRNA-transfected compared with scramble siRNA-transfected VSMCs (P < 0.005 for all). Ex vivo MMP-2 siRNA transfection was performed 2 wk after balloon injury of hypercholesterolemic rabbit carotid arteries. Fluorescence microscopy showed circumferential siRNA uptake in neointimal cells. Gelatin zymography of carotid artery culture medium demonstrated a significant decrease of pro-MMP-2 activity in MMP-2 siRNA-transfected compared with scramble siRNA-transfected arteries (P < 0.01). Overall, our results demonstrate that in vitro MMP-2 siRNA transfection in VSMCs markedly inhibits MMP-2 gene expression and VSMC migration and that ex vivo delivery of MMP-2 siRNA in balloon-injured arteries reduces pro-MMP-2 activity in neointimal cells, suggesting that siRNA could be used to modify arterial biology in vivo.

vascular smooth muscle cell migration; metalloproteinases; balloon-injured arteries


Address for reprint requests and other correspondence: L. J. Feldman, CHU Bichat, Département de Cardiologie, 46, rue Henri Huchard, F-75877 Paris Cedex 18, France (e-mail: laurent.feldman{at}bch.aphp.fr)






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