A monoclonal antibody against alphaVbeta3 integrin inhibits development of atherosclerotic lesions in diabetic pigs.
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.
Maile
Laura A
LA
Division of Endocrinology, University of North Carolina, Chapel Hill, NC 27599-7170, USA.
Busby
Walker H
WH
Nichols
Timothy C
TC
Bellinger
Dwight A
DA
Merricks
Elizabeth P
EP
Rowland
Michael
M
Veluvolu
Umadevi
U
Clemmons
David R
DR
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
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D039302:Integrin alphaVbeta3; D007334:Insulin-Like Growth Factor I