Early growth response gene-1 decoy oligonucleotides inhibit vascular smooth muscle cell proliferation and neointimal hyperplasia of autogenous vein graft in rabbits.

Abstract

The excess proliferation of vascular smooth muscle cells (VSMCs) and the development of intimal hyperplasia is a hallmark of vein graft failure. This study aimed to verify that a single intraoperative transfection of early growth response gene-1 (Egr-1) decoy oligonucleotide (ODN) can suppress vein graft proliferation of VSMCs and intimal hyperplasia. In a rabbit model, jugular veins were treated with Egr-1 decoy ODN, scrambled decoy ODN, Fugene6, or were left untreated, then grafted to the carotid artery. The vein graft samples were obtained 48 h, 1, 2 or 3 weeks after surgery. The thickness of the intima and intima/media ratio in the grafts was analysed by haematoxylin-eosin (HE) staining. The expression of the Egr-1 decoy ODN transfected in the vein was analysed using fluorescent microscopy. Egr-1 mRNA was measured using reverse transcription-polymerase chain reaction. The expression of Egr-1 protein was analysed by Western blot and immunohistochemistry. Transfection efficiency of the ODN was confirmed by 4', 6-diamidino-2-phenylindole staining. In the grafts treated with Egr-1 decoy ODN, our study achieved statistically significant inhibition of intimal hyperplasia by ∼58% at 3 weeks. Transfection of Egr-1 decoy ODNs decreased the protein expression of Egr-1 and Egr-1 mRNA. We confirmed that gene therapy using in vivo transfection of an Egr-1 decoy ODN significantly inhibits proliferation of VSMC and intimal hyperplasia of vein grafts in a rabbit model.