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(Hypertension. 2008;52:86.)
© 2008 American Heart Association, Inc.

Original Articles

Novel Gene Silencer Pyrrole-Imidazole Polyamide Targeting Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Attenuates Restenosis of the Artery After Injury

En-Hui Yao; Noboru Fukuda; Takahiro Ueno; Hiroyuki Matsuda; Koichi Matsumoto; Hiroki Nagase; Yoshiaki Matsumoto; Ayako Takasaka; Kazuo Serie; Hiroshi Sugiyama; Tatsuya Sawamura

From the Division of Nephrology Hypertension and Endocrinology, Department of Medicine (E.-H.Y., N.F., T.U., H.M., K.M.), Division of Cancer Genetics, Department of Advanced Medical Science (H.N.), and Department of Cardiovascular Surgery (A.T.), Nihon University School of Medicine, Tokyo; Advanced Research Institute of the Sciences and Humanities (N.F., H.M., H.N.), Nihon University, Tokyo; Department of Clinical Pharmacokinetics (Y.M.), College of Pharmacy, Nihon University, Chiba; College of Engineering (K.S.), Nihon University Graduate School, Koriyama, Fukushima; Department of Chemistry (H.S.), Graduate School of Science, Kyoto University, Kyoto; and the Department of Vascular Physiology (T.S.), National Cardiovascular Center Research Institute, Osaka, Japan.

Correspondence to Noboru Fukuda, Division of Nephrology Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Ooyaguchi-kami 30-1, Itabashi-ku, Tokyo 173-8610, Japan. E-mail fukudan{at}med.nihon-u.ac.jp

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a membrane protein that can support the binding, internalization, and proteolytic degradation of oxidized low-density lipoprotein. The LOX-1 expression increases in the neointima after balloon injury. To develop an efficient compound to inhibit LOX-1, we designed and synthesized a novel gene silencer pyrrole-imidazole (PI) polyamide targeting the rat LOX-1 gene promoter (PI polyamide to LOX-1) to the activator protein-1 binding site. We examined the effects of PI polyamide to LOX-1 on the LOX-1 promoter activity, the expression of LOX-1 mRNA and protein, and neointimal hyperplasia of the rat carotid artery after balloon injury. PI polyamide to LOX-1 significantly inhibited the rat LOX-1 promoter activity and decreased the expression of LOX-1 mRNA and protein. After balloon injury of the arteries, PI polyamide to LOX-1 was incubated for 10 minutes. Fluorescein isothiocyanate–labeled PI polyamide was distributed to almost all of the nuclei in the injured artery. PI polyamide to LOX-1 (100 µg) significantly inhibited the neointimal thickening by 58%. PI polyamide preserved the re-endothelialization in the injured artery. PI polyamide significantly inhibited the expression of LOX-1, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, and matrix metalloproteinase-9 mRNAs in the injured artery. The synthetic PI polyamide to LOX-1 decreased the expression of LOX-1 and inhibited neointimal hyperplasia after arterial injury. This novel gene silencer PI polyamide to LOX-1 is, therefore, considered to be a feasible agent for the treatment of in-stent restenosis.

Key Words: basic science • endothelium • gene therapy • cytokines • polyamide • LOX-1 • restenosis