Abstract 3079: Overexpression Of Abca1 In Carotid Endothelium Of Hyperlipidemic Rabbits Decreases Vascular Inflammation

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Introduction: Vascular gene therapy that reduces inflammation or increases cholesterol efflux might reduce atherosclerosis. ATP-binding cassette subfamily A member 1 (ABCA1) has both anti-inflammatory and cholesterol efflux activities. We tested whether vessel wall overexpression of ABCA1 would reduce inflammation, vessel wall lipid accumulation, and atherosclerotic lesion size. Methods: We used a helper-dependent adenoviral vector (HDAdABCA1) to overexpress ABCA1 in carotid endothelium of rabbits fed a normal or high-fat diet (HFD). Control arteries received a “Null” vector. We measured ABCA1 expression in transduced carotids of rabbits fed both diets. We used HFD-fed rabbits (n=30) to test whether HDAdABCA1 infusion reduced atherosclerosis. Measurements were made on whole carotid extracts, on extracts of laser-microdissected endothelium, and on histologic sections. Results: At 3 days after infusion, HDAdABCA1 increased whole vessel ABCA1 mRNA by ~2-fold in rabbits fed a normal diet (P=0.07) or a HFD (P=0.04). Endothelial ABCA1 protein was ~1.6-fold higher in HFD-fed rabbits (P=0.06). 24 wks after vector infusion in HFD-fed rabbits, endothelial ABCA1 mRNA was increased (46%; P=0.07), but whole vessel ABCA1 mRNA was slightly decreased (10%; P=0.004). Whole vessel CD68 expression was decreased, as were mRNA encoding several markers of M1-like macrophages: IL-1β: –44%; IL-6: –40%; MCP1: –25%; (P=0.02 for all) and M2-like macrophages: TGF-β1: –13% (P<0.001); ARG-1: –27% (P=0.03); IL-10: –23% (P=0.09). mRNA encoding IL-6 (100%; P<0.001) and TNF-α (P<0.05) was also reduced in endothelium of HDAdABCA1 arteries. Intimal/medial area ratio was slightly less in HDAdABCA1 carotids (–11%; P=0.06). Intimal lipid as well as macrophage and smooth muscle cell content were unchanged (P≥0.5 for all). Mass spectrometry showed no difference in unesterified or esterified cholesterol (P≥0.6 for both). Conclusion: ABCA1 overexpression in carotid endothelium reduced CD68 expression along with levels of several M1- and M2-like macrophage markers and inflammatory cytokines. ABCA1 overexpression had a small effect on intimal mass and did not reduce intimal lipid accumulation. ABCA1 overexpression in endothelium has mild atheroprotective effects.

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