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.
Results and discussion: 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.
Conclusion: These results demonstrate that alphavbeta3 antagonists inhibit signaling, focal adhesion formation and proliferation of insulin-treated HASMC.