Metallic stents are often used to restore blood flow in stenotic coronary arteries. Bare metal stent deployment under high pressure leads to vascular wall and smooth muscle cell (SMC) damage, with subsequent SMC proliferation, neointimal hyperplasia and treatment failure. To combat in-stent restenosis, drug-eluting stents delivering mTOR inhibitors such as sirolimus or everolimus, have become standard of care for coronary stenting. However, these stents typically require long-term dual anti-platelet therapy with aspirin and Plavix (clopidogrel), to prevent thrombotic occlusion of the stented arterial segment. This is due to the relatively non-specific action of mTOR inhibitors: endothelium does not efficiently recover after injury from DESs, rendering the stent struts and arterial lumen vulnerable to platelet activation and thrombosis. Unfortunately, long-term dual anti-platelet therapy leads to increased bleeding/stroke risk and, paradoxically, to increased risk of myocardial infarction. Therefore, finding an alternative drug elution strategy, that would spare endothelium while preventing re-stenosis, would be hugely beneficial to patients with coronary artery disease. Nitric oxide (NO?)-releasing stents, which are still under investigation, are attractive because their mechanism of action inhibits growth of SMC but not EC, and because NO? has a very short diffusion distance, thereby limiting its effects to a localized region. However, to date no stent has succeeded in delivering sufficient doses of NO? to reliably inhibit SMC growth. Since NO? is a selective inhibitor of SMC, how can we increase its potency? For this work, we leverage the fact that NO? increases Fas receptors on the SMC surface, while not having a similar effect on EC. Fas a death-inducing signaling complex upon binding to Fas ligand (FasL). Fas-mediated apoptosis of SMCs is known to decrease hyperplasia significantly in injured vessels. Indeed, the Fas-FasL interaction that kills SMC may create an even more potent DES than do mTOR inhibitors, since mTOR inhibition can arrest cell growth but may not cause apoptosis. Clinically, DES with better SMC inhibition are sorely needed, since current DES still suffer from significant rates of in-stent restenosis after 5 years. Since SMCs are significantly more sensitive to Fas-FasL interaction than are EC, we hypothesize that delivery of both FasL and NO by a next generation stent has the potential to potently block intimal hyperplasia, while retaining EC viability, more efficiently than other DES. This, in turn, could provide a way to shorten post-stent anticoagulation therapy and inhibit in-stent restenosis, thereby decreasing patient risk following coronary stent placement.
The goal of work in this proposal is to evaluate the efficacy of a novel type of drug-eluting arterial stent, for the treatment of patients with atherosclerotic coronary disease. This novel drug combination results in selective growth inhibition of smooth muscle cells, while sparing endothelial cells in the treated vessel. This, in turn, could enhance the effectiveness of coronary artery stenting in the long term.
