Apolipoprotein A-I vascular gene therapy reduces vein-graft atherosclerosis

Abstract

Coronary artery venous bypass grafts typically fail because of atherosclerosis driven by lipid and macrophage accumulation. Therapy for vein-graft atherosclerosis is limited to statin drugs, which are only modestly effective. We hypothesized that transduction of vein-graft endothelium of fat-fed rabbits with a helper-dependent adenovirus expressing apolipoprotein AI (HDAdApoAI) would reduce lipid and macrophage accumulation. Fat-fed rabbits received bilateral external jugular vein-to-carotid artery interposition grafts. Four weeks later, one graft per rabbit (n= 23 rabbits) was infused with HDAdApoAI and the contralateral graft with HDAdNull. Grafts were harvested 12weeks later. Paired analyses of grafts were performed, with vein graft cholesterol, intimal lipid, and macrophage content as the primary endpoints. HDAd genomes were detected in all grafts. APOAI mRNA was median 63-fold higher in HDAdApoAI grafts versus HDAdNull grafts (p<0.001). HDAdApoAI grafts had a mean 15% lower total cholesterol (by mass spectrometry; p= 0.003); mean 19% lower intimal lipid (by oil red O staining; p= 0.02); and mean 13% lower expression of the macrophage marker CD68 (by reverse transcriptase-mediated quantitative PCR; p= 0.008). Invivo transduction of vein-graft endothelium achieves persistent APOAI expression and reduces vein-graft cholesterol, intimal lipid, and CD68 expression. Vascular gene therapy with APOAI haspromise for preventing vein-graft failure caused by atherosclerosis.