Long-term stable expression of human apolipoprotein A-I mediated by helper-dependent adenovirus gene transfer inhibits atherosclerosis progression and remodels atherosclerotic plaques in a mouse model of familial hypercholesterolemia.
BACKGROUND
Epidemiologic studies and transgenic mouse experiments indicate that high plasma HDL and apolipoprotein (apo) A-I protect against atherosclerosis. We used helper-dependent adenovirus (HD-Ad) gene transfer to examine the effect of long-term hepatic apoA-I expression on atherosclerotic lesion progression and remodeling in a mouse model of familial hypercholesterolemia.


RESULTS
We treated LDL receptor-deficient (LDLR-/-) mice maintained on a high-cholesterol diet for 6 weeks with either a HD-Ad containing human apoA-I gene (HD-Ad-AI) or saline (control). HD-Ad-AI treatment did not affect plasma liver enzymes but induced the appearance of plasma human apoA-I at or above human levels for the duration of the study. Substantial amounts of human apoA-I existed in lipid-free plasma. Compared with controls, HDLs from treated mice were larger and had a greater inhibitory effect on tumor necrosis factor-alpha-induced vascular cellular adhesion molecule-1 expression in cultured endothelial cells. Twenty-four weeks after injection, aortic atherosclerotic lesion area in saline-treated mice progressed approximately 700%; the rate of progression was reduced by >50% by HD-Ad-AI treatment. The lesions in HD-Ad-AI-treated mice contained human apoA-I that colocalized mainly with macrophages; they also contained less lipid, fewer macrophages, and less vascular cellular adhesion molecule-1 immunostaining but more smooth muscle cells (alpha-actin staining) and collagen.


CONCLUSIONS
HD-Ad-AI treatment of LDLR-/- mice leads to long-term overexpression of apoA-I, retards atherosclerosis progression, and remodels the lesions to a more stable-appearing phenotype. HD-Ad-mediated transfer of apoA-I may be a useful clinical approach for protecting against atherosclerosis progression and stabilizing atherosclerotic lesions associated with dyslipidemia in human patients.
Department of Medicine, University of Texas Medical Branch, Galveston, Tex, USA.
L Maria
LM
Belalcazar
Aksam
A
Merched
Boyd
B
Carr
Kazuhiro
K
Oka
Kuang-Hua
KH
Chen
Lucio
L
Pastore
Arthur
A
Beaudet
Lawrence
L
Chan
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001011:Aorta / Q000473:pathology; D016632:Apolipoprotein A-I / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D001161:Arteriosclerosis / Q000150:complications / Q000473:pathology / Q000628:therapy*; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary; D004195:Disease Models, Animal; D018450:Disease Progression; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000150:complications* / Q000235:genetics; D007150:Immunohistochemistry; D008075:Lipoproteins, HDL / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D013995:Time; D016896:Treatment Outcome
D016632:Apolipoprotein A-I; D002791:Cholesterol, Dietary; D008075:Lipoproteins, HDL; D011973:Receptors, LDL; D002784:Cholesterol