Published Online
on May 12, 2003

A more recent version of this article appeared on June 3, 2003

This Article Full Text (PDF) All Versions of this Article: 107/21/2726    most recent 01.CIR.0000066913.69844.B2v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Belalcazar, L. M. Articles by Chan, L. Search for Related Content PubMed PubMed Citation Articles by Belalcazar, L. M. Articles by Chan, L. Related Collections Gene therapy

Submitted on November 5, 2002
Revised on February 20, 2003
Accepted on February 28, 2003

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

L. Maria Belalcazar MD, Aksam Merched PhD, Boyd Carr , Kazuhiro Oka PhD, Kuang-Hua Chen PhD, Lucio Pastore MD, PhD, Arthur Beaudet MD, and Lawrence Chan MBBS, DSc^*

From the Department of Medicine (L.M.B., B.C.), University of Texas Medical Branch, Galveston, Tex; Departments of Medicine and Molecular & Cellular Biology (L.M.B., A.M., K.O., K.-H.C., L.C.) and Molecular & Human Genetics (L.P., A.B.), Baylor College of Medicine, Houston, Tex; and St Luke's Episcopal Hospital (L.C.), Houston, Tex.

^* To whom correspondence should be addressed. E-mail: lchan{at}bcm.tmc.edu.

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.

Methods and 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--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 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 (-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.

Key words: gene therapy • apolipoproteins • hypercholesterolemia • atherosclerosis • adenovirus

This article has been cited by other articles:

				J. L. Johnson, A. H. Baker, K. Oka, L. Chan, A. C. Newby, C. L. Jackson, and S. J. George Suppression of Atherosclerotic Plaque Progression and Instability by Tissue Inhibitor of Metalloproteinase-2: Involvement of Macrophage Migration and Apoptosis Circulation, May 23, 2006; 113(20): 2435 - 2444. [Abstract] [Full Text] [PDF]

				M. L. Gruen, M. R. Plummer, W. Zhang, K. A. Posey, M. Linton, S. Fazio, and A. H. Hasty Persistence of high density lipoprotein particles in obese mice lacking apolipoprotein A-I J. Lipid Res., September 1, 2005; 46(9): 2007 - 2014. [Abstract] [Full Text] [PDF]

				R. P. Choudhury, J. X. Rong, E. Trogan, V. I. Elmalem, H. M. Dansky, J. L. Breslow, J. L. Witztum, J. T. Fallon, and E. A. Fisher High-Density Lipoproteins Retard the Progression of Atherosclerosis and Favorably Remodel Lesions Without Suppressing Indices of Inflammation or Oxidation Arterioscler. Thromb. Vasc. Biol., October 1, 2004; 24(10): 1904 - 1909. [Abstract] [Full Text] [PDF]