Abstract 62: Sildenafil Inhibits Neointimal Hyperplasia After Angioplasty, and Reduces Platelet Aggregation

Abstract

Background: Restenosis and stent thrombosis after stent implantation are one of the devating issues in interventional cardiology. Sildenafil has shown its effect in reducing cardiac hypertrophy as well as improving erectile dysfunction through protein kinase G (PKG) activation. Some studies have demonstrated that PKG occupies a central switching role in modulating vascular smooth muscle cell (VSMC) phenotype in response to vascular injury. In this study, we investigated the effects of PKG activation by sidenafil on platelet aggregation and neointimal hyperplasia. Methods and Results: In terms of restenosis after vascular injury, sildenafil significantly reduced neointimal hyperplasia in rat carotid arteries compared to control group. This effect of sildenafil was accompanied by the reduction of viability, cell cycle progression, and migration of VSMCs. This was also confirmed in the injured arteries in vivo. Further studies showed that the increased PKG activity by sildenafil inhibited PDGF-stimulated phenotype change of VSMCs from a contractile to a synthetic form. Conversely, the use of PKG inhibitor or gene transfer of dominant-negative PKG reversed the effects of sildenafil, resulting in the increased viability of VSMCs and neointimal formation. In addition, the mice treated with sidenafil showed the facilitated re-endothelialization, compared to control group. Furthermore, we confirmed the effect of sidenafil through PKG activation using cGK-KO mice. Interestingly, sildenafil significantly inhibited platelet aggregation induced by ADP or thrombin. This effect was reversed by PKG inhibitor, suggesting that sildenafil inhibits platelet aggregation via PKG pathway. Furthermore, assays for VASP phosphorylation and P-selectin activation showed the same inhibitory effect of sildenafil on platelet activation. Conclusions: This study showed that sildenafil inhibits not only platelet aggregation, but also neointimal hyperplasia through the PKG pathway. These findings suggest that sildenafil could be a promising candidate drug of drug-eluting stents for the prevention of restenosis without other complications such as stent thrombosis.