title: Antioxidant protection by PECAM-targeted delivery of a novel NADPH-oxidase inhibitor to the endothelium in vitro and in vivo.
abstract: Oxidant stress caused by pathological elevation of reactive oxygen species (ROS) production in the endothelial cells lining the vascular lumen is an important component of many vascular and pulmonary disease conditions. NADPH oxidase (NOX) activated by pathological mediators including angiotensin and cytokines is a major source of endothelial ROS. In order to intercept this pathological pathway, we have encapsulated an indirect NOX inhibitor, MJ33, into immunoliposomes (Ab-MJ33/IL) targeted to endothelial marker platelet endothelial cell adhesion molecule (PECAM-1). Ab-MJ33/IL, but not control IgG-MJ33/IL are specifically bound to endothelium and attenuated angiotensin-induced ROS production in vitro and in vivo. Additionally, Ab-MJ33/IL inhibited endothelial expression of the inflammatory marker vascular cell adhesion molecule (VCAM) in cells and animals challenged with the cytokine TNF. Furthermore, Ab-MJ33/IL alleviated pathological disruption of endothelial permeability barrier function in cells exposed to vascular endothelial growth factor (VEGF) and in the lungs of mice challenged with lipopolysaccharide (LPS). Of note, the latter beneficial effect has been achieved both by prophylactic and therapeutic injection of Ab-MJ33/IL in animals. Therefore, specific suppression of ROS production by NOX in endothelium, attainable by Ab-MJ33/IL targeting, may help deciphering mechanisms of vascular oxidative stress and inflammation, and potentially improve treatment of these conditions.
authors.affiliation: Department of Pharmacology, University of Pennsylvania, The Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Hood
authors.forename: Colin F
authors.initials: CF
authors.lastname: Greineder
authors.forename: Chandra
authors.initials: C
authors.lastname: Dodia
authors.forename: Jingyan
authors.initials: J
authors.lastname: Han
authors.forename: Clementina
authors.initials: C
authors.lastname: Mesaros
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Shuvaev
authors.forename: Ian A
authors.initials: IA
authors.lastname: Blair
authors.forename: Aron B
authors.initials: AB
authors.lastname: Fisher
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Muzykantov
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D000975:Antioxidants / Q000008:administration & dosage*; D002199:Capillary Permeability / Q000187:drug effects; D004791:Enzyme Inhibitors; D005994:Glycerophosphates / Q000008:administration & dosage*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry / Q000378:metabolism; D008070:Lipopolysaccharides; D008081:Liposomes; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D019809:Streptavidin / Q000737:chemistry; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D000975:Antioxidants; D004791:Enzyme Inhibitors; D005994:Glycerophosphates; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D008081:Liposomes; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II; C078587:1-hexadecyl-3-trifluoroethylglycero-sn-2-phosphomethanol; D019809:Streptavidin; D019255:NADPH Oxidases; D010741:Phospholipases A