Phenotypic correction of hypercholesterolemia in ApoE-deficient mice by adenovirus-mediated in vivo gene transfer

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Abstract

To investigate the potential use of apoE in gone therapy of hyperlipidemias, an adenoviral vector was constructed that contained the human apoE3 cDNA under the control of the RSV promoter (Av1RE). Transduction of HepG2 cells resulted in the overexpression of human apoE secreted into the culture medium. Intravenous injection of 5x1011 Av1RE vector particles into apoE-deficient mice resulted in expression of human apoE3 in mouse plasma at levels of 1.2±0.4 μg/mL (mean±SEM, n=5) 7 days after injection. Mice injected with the control vector Av1Lacz4 did not express detectable levels of human apoE. Average plasma cholesterol concentrations were reduced approximately eightfold from 737.5±118 mg/dL (mean±SEM, n = 6) to 98.2±4.4 mg/dL (mean±SEM, n=5) and were unaffected in the control vector group. Expression of human apoE resulted in a shift in the plasma lipoprotein distribution from primarily VLDL and LDL in the control mice to predominantly HDL in the Av1RE-treated group. Western blot analysis of fast protein liquid chromatography-fractionated mouse plasma showed that the human apoE protein was associated with VLDL, LDL, and HDL. Correction of the hyperlipidemic condition found in the apoE-knockout mouse strain by direct in vivo gene transfer establishes the potential of this approach for treatment of hyperlipidemia caused by apoE deficiency or malfunction in human disease.

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Stevenson, S. C., Marshall-Neff, J., Teng, B., Lee, C. B., Roy, S., & McClelland, A. (1995). Phenotypic correction of hypercholesterolemia in ApoE-deficient mice by adenovirus-mediated in vivo gene transfer. Arteriosclerosis, Thrombosis, and Vascular Biology, 15(4), 479–484. https://doi.org/10.1161/01.ATV.15.4.479

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