Adenovirus-mediated transfer of a gene encoding human apolipoprotein A-I into normal mice increases circulating high-density lipoprotein cholesterol.
BACKGROUND
In animal models of atherosclerosis, augmentation of circulating high-density lipoprotein (HDL) cholesterol exerts a protective effect against development of fatty streaks and promotes plaque regression.


RESULTS
To investigate the potential of gene transfer to increase HDL cholesterol, a fusion gene encoding human apolipoprotein A-I (apo A-I) under the control of the human cytomegalovirus (CMV) immediate-early promoter was packaged into a recombinant adenovirus (AdCMV apo A-I). BALB/c mice infected with AdCMV apo A-I by intravenous injection accumulate immunoreactive apo A-I in serum; levels 5 days after infection averaged 168 mg/dL. A 35% increase in HDL cholesterol and a 47% increase in total cholesterol were observed in mice infected with AdCMV apo A-I compared with control viruses. Analysis of size-fractionated lipoproteins revealed that human apo A-I is incorporated into murine HDL particles. Expression of human apo A-I declined to < 10% of maximum after 12 days and mRNA encoding apo A-I, prevalent 5 days after infection, was undetectable in the livers of infected mice after 12 days.


CONCLUSIONS
We conclude that adenovirus-mediated transfer of a gene encoding apo A-I produces transient elevations of circulating HDL cholesterol of a magnitude correlated with important physiological effects. These observations suggest the potential for gene-based therapeutic strategies to reduce cardiovascular risk.
Kopfler
W P
WP
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-8573.
Willard
M
M
Betz
T
T
Willard
J E
JE
Gerard
R D
RD
Meidell
R S
RS
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D002460:Cell Line / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood*; D003587:Cytomegalovirus / Q000235:genetics; D005260:Female; D018014:Gene Transfer Techniques; D005796:Genes; D008099:Liver / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes / Q000235:genetics; D011995:Recombination, Genetic
D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D015345:Oligonucleotide Probes