Mechanisms in the inhibition of neointimal hyperplasia with triflavin in arat model of balloon angioplasty

RGD-containing peptides are able to inhibit the binding of ligands to certa in beta (3) integrins, such as alpha (IIb)beta (3) and alpha (v)beta (3), b oth of which are involved in neointimal hyperplasia. The present study was designed to elucidate the detailed mechanisms involved in the inhibition of neointimal hyperplasia with triflavin in a rat model of balloon angioplast y. Triflavin (0.25 mg . kg(-1).d(-1)), an RGD-containing disintegrin, time dependently inhibited both neointimal hyperplasia and lumen occlusion after angioplasty in carotid arteries of rats. Furthermore, electron micrographs highlighted that SMCs were phenotypically different from the typical contr actile, spindle-shaped SMCs normally seen in uninjured vessel walls. PDGF-B B was strongly produced in thrombus formation and neointimal SMCs after ang ioplasty, and triflavin significantly reduced PDGF-BB expression in vessel lumens and neointimal SMCs after angioplasty. Balloon angioplasty caused a significant increase of nitrate and cyclic guanosine monophosphate levels c ompared with levels found in sham-operated rats, and these were not signifi cantly changed with infusion of triflavin (0.25 mg . kg(-1) . d(-1)). Furth ermore, the plasma level of TXB2 obviously increased after angioplasty, and triflavin markedly suppressed the elevation of plasma TXB2 concentration. The results indicate that triflavin effectively prevents neointimal hyperpl asia, possibly through the following 2 mechanisms. First, triflavin binds t o alpha (IIb)beta (3) integrin on platelet membranes, resulting in inhibiti on of platelet adhesion, secretion, and aggregation in injured arteries, fo llowed by inhibition of TXA(2) formation and PDGF-BB release from platelets . Second, triflavin may also bind to alpha (v)beta (3) integrin on SMCs, th us subsequently inhibiting cell migration and proliferation. These results provide new insights into the mechanisms of neointimal hyperplasia and have significant implications for disintegrin therapy for the treatment of rest enosis and atherosclerosis.