Apo A-I (Apolipoprotein A-I) Vascular Gene Therapy Provides Durable Protection Against Atherosclerosis in Hyperlipidemic Rabbits. Issue 1 (January 2018)

• Record Type: Journal Article
• Authors: Wacker, Bradley K.; Dronadula, Nagadhara; Bi, Lianxiang; Stamatikos, Alexis; Dichek, David A.
• Is Part Of: Arteriosclerosis, thrombosis, and vascular biology. Volume 38:Issue 1(2018)
• Publication Date: 2018-01
• Subjects: apolipoprotein -- atherosclerosis -- carotid artery -- gene therapy -- rabbits; Arteriosclerosis -- Periodicals; Thrombosis -- Periodicals; Blood-vessels -- Pathophysiology -- Periodicals; Electronic journals; 616.13
• DOI: 10.1161/ATVBAHA.117.309565
• Languages: English
• ISSNs: 1079-5642

Abstract

Abstract : Objective—: Gene therapy that expresses apo A-I (apolipoprotein A-I) from vascular wall cells has promise for preventing and reversing atherosclerosis. Previously, we reported that transduction of carotid artery endothelial cells with a helper-dependent adenoviral (HDAd) vector expressing apo A-I reduced early (4 weeks) fatty streak development in fat-fed rabbits. Here, we tested whether the same HDAd could provide long-term protection against development of more complex lesions. Approach and Results—: Fat-fed rabbits (n=25) underwent bilateral carotid artery gene transfer, with their left and right common carotids randomized to receive either a control vector (HDAdNull) or an apo A-I–expressing vector (HDAdApoAI). Twenty-four additional weeks of high-fat diet yielded complex intimal lesions containing lipid-rich macrophages as well as smooth muscle cells, often in a lesion cap. Twenty-four weeks after gene transfer, high levels of apo A-I mRNA (median ≥250-fold above background) were present in all HDAdApoAI-treated arteries. Compared with paired control HDAdNull-treated arteries in the same rabbit, HDAdApoAI-treated arteries had 30% less median intimal lesion volume ( P =0.03), with concomitant reductions (23%–32%) in intimal lipid, macrophage, and smooth muscle cell content ( P ⩽0.05 for all). HDAdApoAI-treated arteries also had decreased intimal inflammatory markers. VCAM-1 (vascular cell adhesion molecule-1)–stained area was reduced by 36% ( P =0.03), with trends toward lower expression of ICAM-1 (intercellular adhesion molecule-1), MCP-1 (monocyte chemoattractant protein 1), and TNF-α (tumor necrosis factor-α; 13%–39% less; P =0.06–0.1). Conclusions—: In rabbits with severe hyperlipidemia, transduction of vascular endothelial cells with an apo A-I–expressing HDAd yields at least 24 weeks of local apo A-I expression that durably reduces atherosclerotic lesion growth and intimal inflammation. Abstract : Supplemental Digital Content is available in the text.