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 β(3 )integrin inhibitors antagonize fibrinogen binding to α(IIb)β(3 )integrins on platelets and ligand binding to α(v)β(3 )integrins on vascular cells. α(v)β(3 )integrins influence responses to insulin in various cell types but effects in human aortic smooth muscle cells (HASMC) are unknown. RESULTS AND DISCUSSION: Insulin elicited a dose-dependent proliferative response in HASMC. Pretreatment with m7E3 (an anti-β(3 )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 α(IIb)β(3 )but not α(v)β(3), had no effect. Insulin-induced increases in c-Jun NH(2)-terminal kinase-1 (JNK1) activity were partially inhibited by m7E3 and eptifibatide whereas antagonism of α(v)β(3 )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. CONCLUSION: These results demonstrate that α(v)β(3 )antagonists inhibit signaling, focal adhesion formation and proliferation of insulin-treated HASMC.