Eptifibatide and abciximab inhibit insulin-induced focal adhesion formation and proliferative responses in human aortic smooth muscle cells.
BACKGROUND
The use of abciximab (c7E3 Fab) or eptifibatide improves clinical outcomes in diabetics undergoing percutaneous coronary intervention. These beta3 integrin inhibitors antagonize fibrinogen binding to alphaIIbbeta3 integrins on platelets and ligand binding to alphavbeta3 integrins on vascular cells. alphavbeta3 integrins influence responses to insulin in various cell types but effects in human aortic smooth muscle cells (HASMC) are unknown.


CONCLUSIONS
Insulin elicited a dose-dependent proliferative response in HASMC. Pretreatment with m7E3 (an anti-beta3 integrin monoclonal antibody from which abciximab is derived), c7E3 or LM609 inhibited proliferative responses to insulin by 81%, 59% and 28%, respectively. Eptifibatide or cyclic RGD peptides completely abolished insulin-induced proliferation whereas tirofiban, which binds alphaIIbbeta3 but not alphavbeta3, had no effect. Insulin-induced increases in c-Jun NH2-terminal kinase-1 (JNK1) activity were partially inhibited by m7E3 and eptifibatide whereas antagonism of alphavbeta3 integrins had no effect on insulin-induced increases in extracellular signal-regulated kinase (ERK) activity. Insulin stimulated a rapid increase in the number of vinculin-containing focal adhesions per cell and treatment with m7E3, c7E3 or eptifibatide inhibited insulin-induced increases in focal adhesions by 100%, 74% and 73%, respectively.


CONCLUSIONS
These results demonstrate that alphavbeta3 antagonists inhibit signaling, focal adhesion formation and proliferation of insulin-treated HASMC.
Pathak
Alokkumar
A
Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, NC, USA. pathaka@med.unc.edu
Zhao
Renyi
R
Huang
Jianhua
J
Stouffer
George A
GA
D000077284:Abciximab; D015906:Angioplasty, Balloon, Coronary; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003925:Diabetic Angiopathies / Q000628:therapy; D000077542:Eptifibatide; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D022001:Focal Adhesions / Q000187:drug effects*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D007329:Insulin Antagonists / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D007328:Insulin; D007329:Insulin Antagonists; D039302:Integrin alphaVbeta3; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D048055:Mitogen-Activated Protein Kinase 8; D000077542:Eptifibatide; D000077284:Abciximab