Potential roles of osteopontin and alpha(v)beta(3) integrin in the development of coronary artery restenosis after angioplasty

Angioplasty procedures are increasingly used to reestablish blood flow in blocked atherosclerotic coronary arteries, 4 serious complication of these procedures is reocclusion (restenosis), which occurs in 30-50% of patients. Migration of coronary artery smooth muscle cells (CASMCs) to the site of injury caused by angioplasty and subsequent proliferation are suggested mechanisms of reocclusion. Using both cultured human CASMCs and coronary atherectomy tissues, we studied the roles of osteopontin (OPN) and one of its receptors, alpha(v) beta(3) integrin, in the pathogenesis of coronary restenosis. We also measured the plasma levels of OPN before and after angioplasty and determined the effect of exogenous OPN an CASMC migration, extracellular matrix invasion, and proliferation. We found that cultured CASMCs during log phase of growth and smooth muscle cell layer of the coronary atherosclerotic tissues of patients express both OPN mRNA and protein at a significantly elevated level compared with controls, Interestingly, whereas the baseline plasma OPN levels in control samples were virtually undetectable, those in patient plasma were remarkably high, We also found that interaction of OPN with alpha(v) beta(3) integrin, expressed on CASMCs, causes migration, extracellular matrix invasion, and proliferation, These effects were abolished when OPN or alpha(v) beta(3) integrin gene expression in CASMCs was inhibited bg specific antisense S-oligonucleotide treatment or OPN-alpha(v) beta(3) interaction was blocked by treatment of CASMCs with antibodies against OPN or alpha(v) beta(3) integrin, Our results demonstrate that OPN and alpha(v) beta(3) integrin play critical roles in regulating cellular functions deemed essential for restenosis. In addition, these results raise the possibility that transient inhibition of OPN gene expression or blocking of OPN-alpha(v) beta(3) interaction may provide a therapeutic approach to preventing restenosis.