Novel gene silencer pyrrole-imidazole polyamide targeting lectin-like oxidized low-density lipoprotein receptor-1 attenuates restenosis of the artery after injury.
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.
Yao
En-Hui
EH
Division of Nephrology Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Ooyaguchi-kami 30-1, Itabashi-ku, Tokyo 173-8610, Japan.
Fukuda
Noboru
N
Ueno
Takahiro
T
Matsuda
Hiroyuki
H
Matsumoto
Koichi
K
Nagase
Hiroki
H
Matsumoto
Yoshiaki
Y
Takasaka
Ayako
A
Serie
Kazuo
K
Sugiyama
Hiroshi
H
Sawamura
Tatsuya
T
D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology / Q000601:surgery; D002478:Cells, Cultured; D023903:Coronary Restenosis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015195:Drug Design; D015870:Gene Expression / Q000187:drug effects*; D020868:Gene Silencing / Q000187:drug effects; D006965:Hyperplasia / Q000235:genetics / Q000517:prevention & control; D008297:Male; D009757:Nylons / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D011758:Pyrroles / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051127:Scavenger Receptors, Class E / Q000037:antagonists & inhibitors* / Q000235:genetics; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology / Q000601:surgery
D009757:Nylons; D011758:Pyrroles; D012333:RNA, Messenger; D051127:Scavenger Receptors, Class E