Helper-dependent adenoviral vectors are superior in vitro to first-generation vectors for endothelial cell-targeted gene therapy.
Arterial endothelial cells (EC) are attractive targets for gene therapy of atherosclerosis because they are accessible to hematogenous and catheter-based vector delivery and overlie atherosclerotic plaques. Vector-mediated expression-in EC-of proteins that mediate cholesterol transfer out of the artery wall and decrease inflammation could prevent and reverse atherosclerosis. However, clinical application of this strategy is limited by lack of a suitable gene-transfer vector. First-generation adenovirus (FGAd) is useful for EC gene transfer in proof-of-concept studies, but is unsuitable for atheroprotective human gene therapy because of limited duration of expression and proinflammatory effects. Moreover, others have reported detrimental effects of FGAd on critical aspects of EC physiology including proliferation, migration, and apoptosis. Here, we investigated whether helper-dependent adenovirus (HDAd) either alone or expressing an atheroprotective gene [apolipoprotein A-I (apoA-I)] could circumvent these limitations. In contrast to control FGAd, HDAd did not alter any of several critical EC physiologic functions (including proliferation, migration, apoptosis, metabolic activity, and nitric oxide (NO) production) and did not stimulate proinflammatory pathways [including expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and interleukin-6 (IL-6)]. Expression of apoA-I by HDAd reduced EC VCAM-1 expression. HDAd is a promising vector and apoA-I is a promising gene for atheroprotective human gene therapy delivered via EC.
Flynn
Rowan
R
Department of Medicine, University of Washington, Seattle, Washington, USA.
Buckler
Joshua M
JM
Tang
Chongren
C
Kim
Francis
F
Dichek
David A
DA
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D016632:Apolipoprotein A-I / Q000378:metabolism / Q000494:pharmacology*; D002417:Cattle; D015815:Cell Adhesion Molecules / Q000378:metabolism; D016503:Drug Delivery Systems; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism
D015703:Antigens, CD; D016632:Apolipoprotein A-I; D015815:Cell Adhesion Molecules; C065289:ICAM2 protein, human; D009569:Nitric Oxide
J Biol Chem. 2003 Dec 26;278(52):52379-85
14559902
J Virol. 1996 Nov;70(11):7498-509
8892868
Circ Res. 1993 Nov;73(5):797-807
8403251
Exp Cell Res. 1999 Oct 10;252(1):114-22
10502404
Circ Res. 1993 May;72(5):1132-8
8477524
Arterioscler Thromb Vasc Biol. 1998 Dec;18(12):1885-94
9848880
Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13565-70
8942974
J Cell Sci. 2006 Sep 15;119(Pt 18):3788-98
16940353
Br J Cancer. 1984 Apr;49(4):405-13
6201181
Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6482-6
1631146
Hum Gene Ther. 2005 Jan;16(1):1-16
15703484
Arterioscler Thromb. 1993 Feb;13(2):197-204
7678986
Endothelium. 2001;8(3):167-79
11824470
Arterioscler Thromb Vasc Biol. 1998 Nov;18(11):1752-8
9812914
Circulation. 1994 May;89(5):1922-8
7514108
Circulation. 1998 Apr 7;97(13):1274-81
9570198
Mol Ther. 2000 Oct;2(4):381-6
11020354
Circulation. 1998 Nov 3;98(18):1905-11
9799212
J Biol Chem. 2009 Nov 20;284(47):32336-43
19783654
Somat Cell Mol Genet. 1996 Nov;22(6):477-88
9131017
Circulation. 2004 Sep 14;110(11):1484-91
15326058
Hum Gene Ther. 1995 Aug;6(8):1045-53
7578417
Mol Ther. 2009 Feb;17(2):327-33
19050700
Circulation. 2000 Mar 14;101(10):1091-6
10715253
Circulation. 1997 Oct 7;96(7):2254-61
9337198
N Engl J Med. 1999 Jan 14;340(2):115-26
9887164
J Biol Chem. 1985 Nov 25;260(27):14873-8
2997227
Vet Immunol Immunopathol. 2006 Aug 15;112(3-4):272-83
16730378
Antioxid Redox Signal. 2008 Sep;10(9):1631-74
18598143
Blood. 1994 Oct 1;84(7):2068-101
7522621
Circ Res. 2001 May 11;88(9):903-10
11348999
Blood. 1999 May 1;93(9):2936-44
10216088
Mol Ther. 2008 May;16(5):931-41
18388926
Life Sci. 2000 Mar 24;66(18):1683-94
10809165
Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4651-5
1675786
Proc Natl Acad Sci U S A. 2004 May 4;101(18):6999-7004
15107497
Cancer Res. 1968 Aug;28(8):1559-65
4876978
J Biol Chem. 2004 Mar 19;279(12):11760-6
14660586
Circulation. 1996 Jan 15;93(2):301-9
8548903
Circulation. 1996 Apr 1;93(7):1354-63
8641024
Gene Ther. 2003 Jun;10(11):935-40
12756413
Vet Immunol Immunopathol. 2000 Dec 29;77(3-4):275-87
11137125
Nature. 1999 Jun 10;399(6736):597-601
10376602
Microvasc Res. 2007 May;73(3):157-62
17407784
Atherosclerosis. 2008 Jan;196(1):240-247
17586510
Methods. 2005 Oct;37(2):208-15
16288884
Eur J Clin Pharmacol. 1992;42(1):37-41
1541315
J Clin Invest. 1998 Dec 15;102(12):2061-71
9854041
Circ Res. 1987 Dec;61(6):866-79
2890446
Nitric Oxide. 2004 May;10(3):156-61
15158695