Attenuation of carotid neointimal formation after direct delivery of a recombinant adenovirus expressing glucagon-like peptide-1 in diabetic rats

Abstract

Aims Enhancement of glucagon-like peptide-1 (GLP-1) reduces glucose levels and preserves pancreatic b-cell function, but its effect against restenosis is unknown. Methods and results We investigated the effect of subcutaneous injection of exenatide or local delivery of a recombinant adenovirus expressing GLP-1 (rAd-GLP-1) into carotid artery, in reducing the occurrence of restenosis following balloon injury. As a control, we inserted beta-galactosidase cDNA in the same vector (rAd-beta GAL). Otsuka Long-Evans Tokushima rats were assigned to three groups (n = 12 each): (1) normal saline plus rAd-beta GAL delivery (NS+rAd-beta GAL), (2) exenatide plus rAd-beta GAL delivery (Exenatide+rAd-beta GAL), and (3) normal saline plus rAd-GLP-1 delivery (NS+rAd-GLP-1). Normal saline or exenatide were administered subcutaneously from 1 week before to 2 weeks after carotid injury. After 3 weeks, the NS+rAd-beta GAL group showed the highest intima-media ratio (IMR; 3.73 +/- 0.90), the exenatide+rAd-beta GAL treatment was the next highest (2.80 +/- 0.51), and NS+rAd-GLP-1 treatment showed the lowest IMR (1.58 +/- 0.48, P < 0.05 vs. others). The proliferation and migration of vascular smooth muscle cells and monocyte adhesion were decreased significantly after rAd-GLP-1 treatment, showing the same overall patterns as the IMR. In injured vessels, the apoptosis was greater and MMP2 expression was less in the NS+rAd-GLP-1 than in the exenatide or rAd-beta GAL groups. In vitro expressions of matrix metalloproteinases-2 and monocyte chemoattractant protein-1 and nuclear factor-kappa-B-p65 translocation were decreased more in the NS+rAd-GLP-1 group than in the other two groups (all P < 0.05). Conclusion Direct GLP-1 overexpression showed better protection against restenosis after balloon injury via suppression of vascular smooth muscle cell migration, increased apoptosis, and decreased inflammatory processes than systemic exenatide treatment. This has potential therapeutic implications for treating macrovascular complications in diabetes.