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- Apo A-I (Apolipoprotein A-I) Vascular Gene Therapy Provides Durable Protection Against Atherosclerosis in Hyperlipidemic Rabbits.
Apo A-I (Apolipoprotein A-I) Vascular Gene Therapy Provides Durable Protection Against Atherosclerosis in Hyperlipidemic Rabbits.
Citation | “Apo A-I (Apolipoprotein A-I) Vascular Gene Therapy Provides Durable Protection Against Atherosclerosis In Hyperlipidemic Rabbits.”. Arteriosclerosis, Thrombosis, And Vascular Biology, pp. 206-217. . |
Center | University of Washington |
Author | Bradley K Wacker, Nagadhara Dronadula, Lianxiang Bi, Alexis Stamatikos, David A Dichek |
Keywords | apolipoprotein, atherosclerosis, carotid artery, gene therapy, rabbits |
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 (=0.03), with concomitant reductions (23%-32%) in intimal lipid, macrophage, and smooth muscle cell content (≤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% (=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; =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. |
Year of Publication |
2018
|
Journal |
Arteriosclerosis, thrombosis, and vascular biology
|
Volume |
38
|
Issue |
1
|
Number of Pages |
206-217
|
Date Published |
12/2018
|
ISSN Number |
1524-4636
|
DOI |
10.1161/ATVBAHA.117.309565
|
Alternate Journal |
Arterioscler. Thromb. Vasc. Biol.
|
PMID |
29122817
|
PMCID |
PMC5746433
|
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