Targeted detoxification of selected reactive oxygen species in the vascular endothelium.
Oxidative stress underlies diverse vascular diseases, but its management remains elusive, in part because of our inability to selectively detoxify reactive oxygen species (ROS) in pathological sites and our limited understanding which species need to be eliminated. The antioxidant enzymes (AOEs) superoxide dismutase (SOD) and catalase (which decompose and H(2)O(2), respectively), conjugated with an antibody to platelet-endothelial cell adhesion molecule-1 (PECAM-1), bind to endothelial cells and alleviate oxidative stress in cell culture models. Here, we studied the effects of these antioxidant conjugates in mouse models of vascular oxidative stress. Anti-PECAM/catalase and anti-PECAM/SOD conjugates, in contrast to control IgG/AOE conjugates, accumulated in the lungs and vascularized organs after intravenous injection in wild-type, but not PECAM KO mice. Anti-PECAM/catalase, but not anti-PECAM/SOD, protected mice from lung injury induced by H(2)O(2) produced by glucose oxidase deposited in the pulmonary vasculature. Anti-PECAM/catalase also reduced alveolar edema and attenuated decline in arterial oxygen in mice that underwent unilateral lung ischemia/reperfusion, whereas anti-PECAM/SOD was not effective, implying the key role of H(2)O(2) in tissue damage in this pathology. In contrast, anti-PECAM/SOD, but not anti-PECAM/catalase prevented oxidation of tetrahydrobiopterin and normalized vasoreactivity in the vessels of mice rendered hypertensive by pretreatment with angiotensin-II. This outcome agrees with reports implicating superoxide and peroxynitrite in altered endothelium-dependent vasodilatation in hypertension. Therefore, the use of endothelial cell-targeted antioxidants identifies the key specific species of ROS involved in various forms of vascular disease and holds promise for the mechanistically tailored treatment of these pathologies.
Shuvaev
Vladimir V
VV
Institute for Environmental Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6068, USA.
Christofidou-Solomidou
Melpo
M
Bhora
Faiz
F
Laude
Karine
K
Cai
Hua
H
Dikalov
Sergei
S
Arguiri
Evguenia
E
Solomides
Charalambos C
CC
Albelda
Steven M
SM
Harrison
David G
DG
Muzykantov
Vladimir R
VR
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000378:metabolism / Q000494:pharmacology*; D000975:Antioxidants / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001708:Biopterins / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002374:Catalase / Q000008:administration & dosage / Q000494:pharmacology*; D003432:Cross-Linking Reagents; D004730:Endothelium, Vascular / Q000378:metabolism*; D005949:Glucose Oxidase / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism; D008171:Lung Diseases / Q000139:chemically induced / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology; D011652:Pulmonary Circulation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism* / Q000633:toxicity*; D015427:Reperfusion Injury / Q000517:prevention & control; D013482:Superoxide Dismutase / Q000008:administration & dosage / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism
D000906:Antibodies; D000975:Antioxidants; D003432:Cross-Linking Reagents; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D017382:Reactive Oxygen Species; D013481:Superoxides; D000804:Angiotensin II; D001708:Biopterins; D006861:Hydrogen Peroxide; D005949:Glucose Oxidase; D002374:Catalase; D013482:Superoxide Dismutase
Semin Immunopathol. 2008 Jul;30(3):193-4
18560833
Am J Physiol Lung Cell Mol Physiol. 2000 Mar;278(3):L504-11
10710522
J Clin Invest. 1997 Jan 1;99(1):3-8
9011572
Arterioscler Thromb Vasc Biol. 2007 Apr;27(4):762-8
17272743
Free Radic Biol Med. 2003 Aug 1;35(3):213-25
12885584
J Nutr. 2006 Jun;136(6):1545-51
16702319
Cardiovasc Res. 2005 Oct 1;68(1):26-36
16009356
Antioxid Redox Signal. 2007 Nov;9(11):1991-2002
17760509
Arch Physiol Biochem. 2007 Feb;113(1):1-12
17522980
Am J Physiol Heart Circ Physiol. 2007 Dec;293(6):H3720-5
17965288
J Biol Chem. 2003 Jun 20;278(25):22546-54
12692136
J Hum Hypertens. 2008 Jun;22(6):401-7
18322548
J Pharmacol Exp Ther. 2007 Apr;321(1):18-27
17210799
Prostaglandins Other Lipid Mediat. 2007 Jan;82(1-4):119-27
17164139
J Clin Invest. 1989 Apr;83(4):1326-35
2467923
Ann Med. 2007;39(4):275-89
17558599
Proc Natl Acad Sci U S A. 2004 Nov 23;101(47):16403-4
15546989
Trends Pharmacol Sci. 2003 Sep;24(9):471-8
12967772
Anal Biochem. 1980 Feb;102(1):176-88
7356152
Expert Opin Drug Deliv. 2005 Sep;2(5):909-26
16296786
Am J Physiol Lung Cell Mol Physiol. 2007 Jul;293(1):L162-9
17435080
J Control Release. 2001 Mar 12;71(1):1-21
11245904
Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3362-6
1314387
J Control Release. 2007 Apr 2;118(2):235-44
17270308
Am J Physiol Lung Cell Mol Physiol. 2006 Nov;291(5):L1050-8
16815892
Am J Respir Crit Care Med. 2003 Apr 1;167(7):1027-35
12663342
Am J Physiol Lung Cell Mol Physiol. 2003 Aug;285(2):L283-92
12851209
Am J Physiol Lung Cell Mol Physiol. 2003 Jun;284(6):L917-25
12736188
Proc Natl Acad Sci U S A. 1996 May 28;93(11):5213-8
8643555
Free Radic Biol Med. 2003 Apr 15;34(8):1035-46
12684088
Methods Enzymol. 2002;349:331-41
11912924
J Biol Chem. 1999 Feb 19;274(8):4985-94
9988743
Circ Res. 2004 Nov 26;95(11):1075-81
15528470
Am J Physiol Lung Cell Mol Physiol. 2008 Feb;294(2):L255-65
18083772
Nat Biotechnol. 2003 Apr;21(4):392-8
12652312
J Pharmacol Exp Ther. 2005 Dec;315(3):1058-64
16144972
J Pharmacol Exp Ther. 2007 Nov;323(2):450-7
17712041
Hypertension. 2007 Apr;49(4):717-27
17296874
Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2379-84
10051650
J Clin Invest. 2003 Apr;111(8):1201-9
12697739