Document Detail

Novel gene silencer pyrrole-imidazole polyamide targeting lectin-like oxidized low-density lipoprotein receptor-1 attenuates restenosis of the artery after injury.
MedLine Citation:
PMID:  18519843     Owner:  NLM     Status:  MEDLINE    
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 microg) 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.
En-Hui Yao; Noboru Fukuda; Takahiro Ueno; Hiroyuki Matsuda; Koichi Matsumoto; Hiroki Nagase; Yoshiaki Matsumoto; Ayako Takasaka; Kazuo Serie; Hiroshi Sugiyama; Tatsuya Sawamura
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-06-02
Journal Detail:
Title:  Hypertension     Volume:  52     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2008 Jul 
Date Detail:
Created Date:  2008-06-20     Completed Date:  2008-07-08     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  86-92     Citation Subset:  IM    
Division of Nephrology Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Ooyaguchi-kami 30-1, Itabashi-ku, Tokyo 173-8610, Japan.
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MeSH Terms
Angioplasty, Balloon / adverse effects
Carotid Arteries / drug effects,  pathology,  surgery
Cells, Cultured
Coronary Restenosis / genetics,  pathology,  prevention & control*
Drug Design
Gene Expression / drug effects*
Gene Silencing / drug effects
Hyperplasia / genetics,  prevention & control
Nylons / chemical synthesis,  chemistry,  pharmacology*
Promoter Regions, Genetic / drug effects
Protein Biosynthesis / drug effects
Pyrroles / chemical synthesis,  pharmacology*,  therapeutic use
RNA, Messenger / metabolism
Rats, Wistar
Scavenger Receptors, Class E / antagonists & inhibitors*,  genetics
Tunica Intima / drug effects*,  pathology,  surgery
Reg. No./Substance:
0/Nylons; 0/Pyrroles; 0/RNA, Messenger; 0/Scavenger Receptors, Class E

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