title: A monoclonal antibody against alphaVbeta3 integrin inhibits development of atherosclerotic lesions in diabetic pigs.
abstract: Atherosclerotic lesions develop and progress more rapidly in diabetic patients than in nondiabetic individuals. This may be caused by accelerated lesion formation in the high-glucose environment of diabetes. Smooth muscle cells (SMCs) cultured in high glucose are more responsive to growth factors such as insulin-like growth factor-1 (IGF-1). This enhanced response to IGF-1 is due in part to increased activation of the alpha(V)beta(3) integrin. We tested whether alpha(V)beta(3) integrin activation was increased in diabetic animals and whether an antibody to beta(3) would inhibit IGF-1 action and development of atherosclerosis. Eight male pigs were made diabetic with streptozotocin and fed a high-fat diet. A F(ab)(2) antibody fragment directed at beta(3) was infused into one femoral artery, whereas the other artery received control F(ab)(2) for 3.5 months. There was a 65 +/- 8% reduction in atherosclerotic lesion area in the arteries treated with F(ab)(2) antibody to beta(3). Phosphorylation of beta(3) was reduced by 75 +/- 18% in vessels treated with the antibody. Shc and mitogen-activated protein kinase phosphorylation, which are required for IGF-1-stimulated SMC proliferation, were also significantly reduced. We conclude that activation of IGF-1 receptor and alpha(V)beta(3)-linked signaling pathways accelerates atherosclerosis in diabetes and that administration of an antibody to beta(3) to diabetic pigs inhibits alpha(V)beta(3) activation, IGF-1-stimulated signaling, and atherosclerotic lesion development. This approach offers a potential therapeutic approach to the treatment of this disorder.
authors.affiliation: Division of Endocrinology, University of North Carolina, Chapel Hill, NC 27599-7170, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Maile
authors.forename: Walker H
authors.initials: WH
authors.lastname: Busby
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Nichols
authors.forename: Dwight A
authors.initials: DA
authors.lastname: Bellinger
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Merricks
authors.forename: Michael
authors.initials: M
authors.lastname: Rowland
authors.forename: Umadevi
authors.initials: U
authors.lastname: Veluvolu
authors.forename: David R
authors.initials: DR
authors.lastname: Clemmons
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology*; D050197:Atherosclerosis / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D005263:Femoral Artery / Q000378:metabolism / Q000473:pathology; D007140:Immunoglobulin Fab Fragments; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000276:immunology*; D008297:Male; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D013552:Swine; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D039302:Integrin alphaVbeta3; D007334:Insulin-Like Growth Factor I