Abstract 15151: Novel Tiplaxtinin Eluting Stent Inhibits the Migration of Vascular Smooth Muscle Cells but not Endothelial Cells
Introduction: Plasminogen activator inhibitor-1 (PAI-1), a key regulator of the plasminogen activator system and fibrinolysis, also regulates vascular remodeling. Elevated levels of PAI-1 are associated with the development of intimal hyperplasia. The goals of this study were to develop and characterize intravascular stents capable of eluting a pharmacological inhibitor of PAI-1, tiplaxtinin, and to study their effects on vascular smooth muscle cells (SMC) and human coronary artery endothelial cells (HCAEC) in vitro.
Methods and Results: Tiplaxtinin was coated on stainless steel stents with a spray apparatus using polylactic-co-glycolic acid as the binding polymer. Scanning electron microscopy revealed uniform stent coating. HPLC analysis of aqueous eluates of tiplaxtinin-coated stents revealed sustained elution of tiplaxtinin from stents for up to 21 days. To determine if tiplaxtinin eluting from stents retained activity and inhibited SMC or HCAEC migration, tiplaxtinin- and vehicle-control-coated stents (TES and VCS, respectively) were placed in transwell cell migration apparati along with SMC or HCAEC. PDGF-BB-induced cell migration was measured. TES inhibited human coronary artery SMC migration by 89.1±10.2 % compared to control (p <0.001; n=3/group). TES also inhibited migration of SMC isolated from wild-type mice by 44.1±28.3% (p=0.01; n=3/group), but had no significant effect on migration of SMC isolated from PAI-1-deficient mice, suggesting that TES inhibited SMC migration by a PAI-1-specific mechanism. In contrast, TES had no signicant effect on the migration of HCAEC (migration of HCAEC in presence of TES was 96±15.3% that of VCS controls, p =0.87; n=3/group).
Conclusions: Tiplaxtinin, a low-molecular-weight, specific PAI-1 inhibitor, can be coated on stents, elute from them with a favorable pharmacological profile, and inhibit SMC migration without inhibiting endothelial cells migration. TES should prove useful for studying the role of PAI-1 in vascular remodeling in large animal models of neointima formation, and may have efficacy as a therapeutic strategy to inhibit restenosis.
- © 2012 by American Heart Association, Inc.