© 1997 American Heart Association, Inc.
Articles |
Effective Lowering of Plasma, LDL, and Esterified Cholesterol in LDL Receptor–Knockout Mice by Adenovirus-Mediated Gene Delivery of ApoB mRNA Editing Enzyme (Apobec1)
From the Department of Medicine, Baylor College of Medicine, Houston, Tex (B.B.T., S.B., L-Z.S., A.M.G., L.C.); the Department of Medicine, University of California, San Francisco (B.I.); and the Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, Calif (T.M.F.).
Correspondence to BaBie Teng, PhD, Department of Medicine, Section of Atherosclerosis and Lipoprotein Research, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. E-mail teng{at}bcm.tmc.edu
Abstract Adenovirus-mediated gene delivery of apolipoprotein (apo)B mRNA editing enzyme (AvApobec1) was used to study the effect of apoB mRNA editing on apoB production in homozygous LDL receptor–deficient (LDLR-/-) mice. Intravenous injection of AvApobec1 into these mice resulted in a >80% decrease in plasma apoB-100 with a concomitant increase in plasma apoB-48 level. The plasma apoE level also increased. In all cases, total plasma apoB (apoB-100 + apoB-48) decreased by 60% at day 5 and remained 
40% lower in AvApobec1-treated compared with control vector Av1LacZ4–treated animals at day 12. On day 12, total plasma cholesterol decreased by 29% in male mice and 18% in female mice that were transduced with AvApobec1. This was reflected in a reduction in apoB-containing lipoprotein cholesterol, which decreased by 34% and 27% in male and female mice, respectively. Apobec1 gene transfer also decreased the cholesteryl ester contents in the LDL fraction, which were 16%, 22%, and 22% in female and 20%, 20%, and 15% in male animals on days 5, 7, and 12, respectively, compared with Av1LacZ controls with 29%, 32%, and 33%, respectively, in female and 29%, 38%, and 36%, respectively, in male animals. Nondenaturing gradient gel electrophoresis indicated almost complete elimination of LDL particles of 29, 27, and 25 nm at days 7 and 12. We conclude that in the absence of a functioning LDL receptor, hepatic overexpression of Apobec1 is highly efficient in lowering plasma apoB-100 levels, leading to the almost complete elimination of LDL particles and a reduction in LDL cholesterol and cholesteryl ester content.
Key Words: gene therapy • LDL receptor–deficient mouse • apoB mRNA editing • hypercholesterolemia • lipoproteins
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