Adeno-associated virus-mediated expression of acid sphingomyelinase decreases atherosclerotic lesion formation in apolipoprotein E−/− mice

Autor: Rod Moreland, Seng H. Cheng, Nelson S. Yew, Peter A. Piepenhagen, Canwen Jiang, Lingyun Li, Akihiro Urabe, Robin J. Ziegler, Andrew Leger, Zhengyu Luo, Joshua Pacheco, Wei-Lien Chuang, Leocadia M. Mosquea, Kristin M. Taylor
Rok vydání: 2011
Předmět:
Zdroj: The Journal of Gene Medicine. 13:324-332
ISSN: 1099-498X
Popis: Background The secretory form of acid sphingomyelinase (ASM) is postulated to play a key role in the retention and aggregation of lipoproteins in the subendothelial space of the arterial wall by converting sphingomyelin in lipoproteins into ceramide. The present study aimed to determine whether the level of circulating ASM activity affects lesion development in mouse model of atherosclerosis. Methods Apolipoprotein E deficient (ApoE−/−) mice were injected intravenously with a recombinant adeno-associated virus (AAV8-ASM) that constitutively expressed high levels of human ASM in liver and plasma. Results Plasma sphingomyelin levels were reduced at early but not later time points after the administration of AAV8-ASM despite persistently elevated circulating ASM. No change in serum lipoprotein levels was observed. Thirteen or 17 weeks after the administration of AAV8-ASM, the amount of plaque formation in the aortic sinus was comparable to that of mice treated with a control AAV. Conclusions Unexpectedly, the lesion area of the entire aorta was reduced significantly in the AAV8-ASM virus-treated group. Hepatic expression and secretion of ASM into the circulation did not accelerate or exacerbate, but rather decreased, lesion formation in ApoE−/− mice. Thus, plasma ASM activity does not appear to be rate limiting for plaque formation during atherogenesis. Copyright © 2011 John Wiley & Sons, Ltd.
Databáze: OpenAIRE
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