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Abstract 444: Apolipoprotein A-I (ApoAI) Vascular Gene Therapy Protects Against Vein-Graft Atherosclerosis


 Introduction:
 Coronary artery venous bypass grafts typically fail because of accelerated atherosclerosis, driven by lipid infiltration and by accumulation of macrophages and other cells. We previously showed that transduction of carotid artery endothelium of fat-fed rabbits with a helper-dependent adenovirus expressing apolipoprotein AI (HDAdApoAI) reduced atherosclerotic lesion size and decreased intimal lipid and macrophage accumulation. We hypothesized that HDAdApoAI transduction of rabbit vein graft endothelium would reduce lipid and macrophage accumulation.
 
 
 Methods:
 Fat-fed rabbits received bilateral external jugular vein to carotid artery interposition grafts. Four wks later, one graft per rabbit was infused with HDAdApoAI and the other with HDAdNull (a non-expressing HDAd). Grafts were harvested 12 wks after HDAd infusion. Paired analysis was performed in all rabbits with bilateral patent grafts (n=22). Graft hemodynamics were measured at vector-infusion and harvest surgeries. In vivo graft diameters were measured before vector infusion and harvest with ultrasound. Grafts were cut into 8 segments, for histology and biochemical analyses.
 
 
 Results:
 Mean plasma cholesterol levels were 400-600 mg/dL. Graft patency rates were 89% after vein grafting and 100% after the vector-infusion surgery. Lumen diameter and hemodynamics did not differ between HDAdApoAI and HDAdNull-transduced grafts. HDAd genomes were detected in all vein grafts. High levels of apoAI mRNA were detected in 100% of HDAdApoAI-treated vein grafts (mean 155-fold higher than in HDAdNull grafts). HDAdApoAI-treated grafts had 25% lower cholesterol (by mass spectrometry; P=0.03) and 17% less median CD68 mRNA (by RT-qPCR; P=0.008; CD68 is expressed by macrophages and lipid-loaded SMC). No significant differences were detected in mRNA encoding several inflammatory cytokines and inflammation-associated proteins. There were nominal decreases in total intimal area (16%, P=0.9), percent stenosis (4%, P=0.08), and in intimal area positive for Oil Red O (11%, P=0.3), macrophages (11%, P=0.7), and VCAM-1 (8%, P=0.8).
 
 
 Conclusion:
 HDAdApoAI transduction of vein graft endothelium reduces some markers of atherosclerosis, potentially by stimulating cholesterol efflux.
