Fas ligand and nitric oxide combination to control smooth muscle growth while sparing endothelium.

Abstract

Metallic stents cause vascular wall damage with subsequent smooth muscle cell (SMC) proliferation, neointimal hyperplasia, and treatment failure. To combat in-stent restenosis, drug-eluting stents (DES) delivering mTOR inhibitors such as sirolimus or everolimus have become standard for coronary stenting. However, the relatively non-specific action of mTOR inhibitors prevents efficient endothelium recovery and mandates dual antiplatelet therapy to prevent thrombosis. Unfortunately, long-term dual antiplatelet therapy leads to increased risk of bleeding/stroke and, paradoxically, myocardial infarction. Here, we took advantage of the fact that nitric oxide (NO) increases Fas receptors on the SMC surface. Fas forms a death-inducing complex upon binding to Fas ligand (FasL), while endothelial cells (ECs) are relatively resistant to this pathway. Selected doses of FasL and NO donor synergistically increased SMC apoptosis and inhibited SMC growth more potently than did everolimus or sirolimus, while having no significant effect on EC viability and proliferation. This differential effect was corroborated in ex vivo pig coronaries, where the neointimal formation was inhibited by the drug combination, but endothelial viability was retained. We also deployed FasL-NO donor-releasing ethylene-vinyl acetate copolymer (EVAc)-coated stents into pig coronary arteries, and cultured them in perfusion bioreactors for one week. FasL and NO donor, released from the stent coating, killed SMCs close to the stent struts, even in the presence of flow rates mimicking those of native arteries. Thus, the FasL-NO donor-combination has a potential to prevent intimal hyperplasia and in-stent restenosis, without harming endothelial restoration, and hence may be a superior drug delivery strategy for DES.

• Authors: Mehmet H Kural, Juan Wang, Liqiong Gui, Yifan Yuan, Guangxin Li, Katherine L Leiby, Elias Quijano, George Tellides, W Mark Saltzman, Laura E Niklason
• Journal: Biomaterials (Biomaterials) Vol. 212 Pg. 28-38 (08 2019) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 31102854 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019. Published by Elsevier Ltd.

Chemical References

• Fas Ligand Protein
• Nitroso Compounds
• Polymers
• 2,2'-(hydroxynitrosohydrazono)bis-ethanamine
• Nitric Oxide
• Everolimus
• Sirolimus

Topics

• Animals
• Bioreactors
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cells, Cultured
• Coronary Vessels (cytology)
• Endothelial Cells (cytology, drug effects)
• Everolimus (pharmacology)
• Fas Ligand Protein (pharmacology)
• Gene Expression Regulation (drug effects)
• Humans
• Kinetics
• Myocytes, Smooth Muscle (cytology, drug effects)
• Nitric Oxide (pharmacology)
• Nitroso Compounds (pharmacology)
• Polymers (chemistry)
• Sirolimus (pharmacology)
• Swine