Abstract

Objective: Drug eluting stents have recently been associated with the increased risk of adverse thrombogenic events and/or late luminal loss, which is highly associated with incomplete re-endothelialization. The increased risks behoove the design of alternative delivery modalities and/or drugs that do not compromise the re-endotheliaization process. The objective of the present study is to elucidate the biological mechanism(s) by which non-stent-based delivery modalities for the anti-proliferative lipid metabolite, C6-ceramide, could lead to a reduction in arterial injury after angioplasty. Results: Immunohistochemical studies in rabbit and porcine models suggest that C6-ceramide-coated balloon catheters limit arterial stenosis without inhibiting endothelial wound healing responses. Specifically, C6-ceramide-coated balloon catheters reduce internal elastica injury with a corresponding reduction in medial fracture length in a 28-day porcine coronary artery stretch model. In addition, C6-ceramide decreases the formation of the fibrin matrix to possibly augment the subsequent wound healing response. We hypothesized that differential metabolism of exogenous ceramide by coronary endothelial and smooth muscle cells could explain the apparent discrepancy between the anti-proliferative actions of ceramide and the pro-wound healing responses of ceramide. Human coronary artery endothelial cells (HCAEC), in contrast to human coronary artery smooth muscle cells (HCASMC), preferentially express ceramide kinase and form ceramide-1- phosphate, which promotes endothelial cell survival. Conclusion: Differential metabolism of ceramide between HCASMC and HCAEC offers a mechanism by which ceramide preferentially limits smooth muscle cell growth, in the presence of active wound healing. The combinatorial ability of ceramide to limit vascular smooth muscle proliferation and promote re-endothelialization, offers the potential for C6- ceramide-coated catheters to serve as adjuncts to stent-based modalities or as a stand-alone treatment.

Keywords: C6-Ceramide-Coated Catheters, Re-Endothelialization, Stretch- Injured Arteries, anti-proliferative lipid metabolite, Immunohistochemical studies, fibrin matrix, Human coronary artery endothelial cells (HCAEC)