J. Lipid Res.
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A more recent version of this article appeared on June 1, 2006

Papers In Press, published online ahead of print February 28, 2006
J. Lipid Res., doi:10.1194/jlr.M600040-JLR200
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Submitted on January 25, 2006
Revised on February 21, 2006
Accepted on February 28, 2006

Adenovirus-mediated overexpression of sphingomyelin synthase 1 and 2 increases the atherogenic potential in mice

Jibin Dong, Jing Liu, Bin Lou, Zhiqiang Li, Xun Ye, Manping Wu, and Xian-Cheng Jiang

Anatomy and Cell Biology, SUNY, Brooklyn, NY 11203

Corresponding Author: xjiang{at}downstate.edu

SMS1 and SMS2 are two isoforms of sphingomyelin (SM) synthase, the last enzyme for SM biosynthesis. To evaluate the role of SMS in vivo in terms of plasma lipoprotein metabolism, we generated adenoviruses which carry human SMS1 (AdV-SMS1), SMS2 (AdV-SMS2), and the reporter LacZ (AdV-LacZ), respectively. On day 7 after intravenous infusion of the adenoviruses into mice, liver SMS1 and SMS2 mRNA levels as well as SMS activity were significantly increased. Lipoprotein analysis indicated that AdV-SMS1 and AdV-SMS2 treatment caused significant decrease of SM and cholesterol in HDL (42% and 38%; 27% and 25%, p<0.05, respectively), significant increase of SM and cholesterol in non-HDL (50% and 35 %, 64% and 61%, p<0.05, respectively), and significant increase of apoB (p<0.01) but not apoA-I, compared with AdV-LacZ controls. Moreover, we found that non-HDL from both AdV-SMS1- and AdV-SMS2-treated mice were significantly aggregated after treatment with a mammalian sphingomyelinase, whereas these lipoproteins from control animals did not aggregate. To investigate the mechanism of HDL changes, we measured liver scavenger receptor BI (SR-BI) levels by Western blot. We found that AdV-SMS1 and AdV-SMS2 mouse liver homogenates contain 70% and 75% higher SR-BI levels than in controls, while no change was observed in hepatic ATP Binding Cassette Transporter AI levels. HDL turnover study revealed an increase of plasma-clearance rates for [3H]CEt-HDL but not for [125I]HDL in both AdV-SMS1 and SMS2 mice compared with controls. In conclusion, adenovirus-mediated human SMS1 and SMS2 expression increased lipoprotein atherogenic potential. Such an effect may contribute to the elevated plasma SM levels observed in animal models for atherosclerosis, and in human patients with coronary artery disease.


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