Abstract 17407: Favorable Modulation of Atherosclerosis and Monocyte Phenotype by Intravenous AAV 8 Mediated Apo A-I Milano Gene Transfer in Mice
Background: We evaluated the effects of intravenously administered rAAV8 encoding Apo A-I Milano on aortic and innominate artery atherosclerosis, plaque composition and phenotype of circulating mononuclear cells in Apo E−/− Apo A1−/− mice.
Methods: Mice received one intravenous injection of 1.2x1012 vector genome copies of rAAV8 - Milano or empty vector (12 mice per group). Four weeks after injection mice were placed on high fat diet. Twenty weeks later mice were euthanized and the extend of atherosclerosis in the aorta, aortic sinuses, and innominate artery was measured. Oil-red o staining and Moma-2 staining were used to measure lipid content and macrophage content of the plaques respectively. Quantitative PCR (qPCR) was used to analyze phenotype of macrophages.
Results: Compared to vector control, the Milano recipients had less atherosclerosis in whole aorta (13.4 ± 1.1 % vs. 7.7 ± 0.06%, p= 0.001), in aortic sinuses (77.1 ±9.6 vs 44.8 ±2.3,p=0.01 ) and in the innominate artery (12.4 ± 2.4 vs 4.4 ± 2.1 mm2; p<0.05). These effects were associated with reduced plaque lipid content in aortic sinuses (20.3±vs 12.8 ± 2.3 % p=0.03) and in innominate artery (14.4 ± 2.5 vs 5.3 ± 1.6 %; p=0.001) and reduced plaque macrophage content in aortic sinuses (20.9 ±2.1 vs 11.7 ±2.4 %, p=0.02) and in innominate arteries (8.3 ± 1.5 vs 3.1 ± 1.1% p=0.01). Compared to vector control, the Milano recipients showed reduced mRNA levels of M1 markers (MCP-1 and TNF-α) and increased expression level of M2 marker Arg-1 in circulating mononuclear cells.
Conclusions: rAAV8 mediated Apo A-I Milano gene transfer reduces plaque in whole aorta, aortic sinuses and innominate arteries with a more stable plaque phenotype and an anti-inflammatory phenotype in circulating mononuclear cells.
- © 2010 by American Heart Association, Inc.