Abstract 16451: Quinacrine as a Novel Anti-Restenotic and Anti-Thrombotic Drug for Coronary Artery Interventions
Background Coronary drug eluting stents (DES) have significantly reduced the rate of in-stent restenosis, but have also increased the rate of vessel thrombosis and, in turn, the duration of dual antiplatelet therapy. Since delayed vessel endothelialization has been advocated as a major factor promoting vessel thrombosis after DES implantation, in this study we tested whether a different pharmacological approach could be undertaken, reducing smooth muscle cells (SMC) proliferation with minor (if any) effects on endothelial cells (EC) or thrombosis.
Methods To test this, we first evaluated the in vitro effects of the acridine derivative quinacrine (Q, 0.2, 2 and 5 uM) on human SMC and EC, tissue factor (TF) and cell-adhesion molecules expression. Next, in order to test in vivo Q effects, a rat model of carotid injury was used, and Q (2 uM) was locally administered after the artery angioplasty in a pluronic gel solution.
Results In human SMC, Q increased p53 expression and induced apoptosis at all concentrations, as shown by propidium iodide (Figure, *p<0.05 vs. respective control, CN, **p<0.05 vs. all), Tunel and Annexin V stainings. In contrast, EC apoptosis was observed only at the highest doses (5 uM, Figure), and p53 levels were never induced by Q treatment. After in vivo carotid artery injury, Q induced p53 levels and apoptosis in the neointima, and reduced both neointimal area and neointima/media ratio without affecting re-endothelialization of injured vessels. In contrast to Paclitaxel, Q did not induce TF activity or the expression of cellular adhesion molecules.
Conclusions In conclusion, Q exerts pro-apoptotic effects with higher selectivity for SMC, in the absence of pro-thrombotic effects. Thus, it might represent a novel therapeutic strategy for coronary artery interventions.
- © 2011 by American Heart Association, Inc.