Abstract
BackgroundDrug-eluting stents (DES) have dramatically reduced restenosis rates compared to bare metal stents and are widely used in coronary artery angioplasty. The anti-proliferative nature of the drugs reduces smooth muscle cell (SMC) proliferation effectively, but unfortunately also negatively affects endothelialization of stent struts, necessitating prolonged dual anti-platelet therapy. Cell-type specific therapy may prevent this complication, giving rise to safer stents that do not require additional medication. 6-Mercaptopurine (6-MP) is a drug with demonstrated cell-type specific effects on vascular cells both in vitro and in vivo, inhibiting proliferation of SMCs while promoting survival of endothelial cells. In rabbits, we demonstrated that DES locally releasing 6-MP during 4 weeks reduced in-stent stenosis by inhibiting SMC proliferation and reducing inflammation, without negatively affecting endothelialization of the stent surface. The aim of the present study was to investigate whether 6-MP-eluting stents are similarly effective in preventing stenosis in porcine coronary arteries after 3 months, in order to assess the eligibility for human application.Methods6-MP-eluting and polymer-only control stents (both n = 7) were implanted in porcine coronary arteries after local balloon injury to assess the effect of 6-MP on vascular lesion formation. Three months after implantation, stented coronary arteries were harvested and analyzed.ResultsMorphometric analyses revealed that stents were implanted reproducibly and with limited injury to the vessel wall. Unexpectedly, both in-stent stenosis (6-MP: 41.1 ± 10.3 %; control: 29.6 ± 5.9 %) and inflammation (6-MP: 2.14 ± 0.51; control: 1.43 ± 0.45) were similar between the groups after 3 months.ConclusionIn conclusion, although 6-MP was previously found to potently inhibit SMC proliferation, reduce inflammation and promote endothelial cell survival, thereby effectively reducing in-stent restenosis in rabbits, stents containing 300 μg 6-MP did not reduce stenosis and inflammation in porcine coronary arteries.
Highlights
Drug-eluting stents (DES) have dramatically reduced restenosis rates compared to bare metal stents and are widely used in coronary artery angioplasty
Stents loaded with a drug having a cell-type specific mechanism of action may effectively inhibit smooth muscle cell (SMC) proliferation and reduce restenosis without negatively interfering in the process of re-endothelialization of the stented artery segment, giving rise to safer stents and lower risk of the occurrence of thrombotic events
Based on this knowledge we hypothesize that targeting Nur77 is an interesting approach to prevent in-stent restenosis, while promoting re-endothelialization and reducing local inflammation and thrombosis. 6-Mercaptopurine (6-MP) is a well-documented activator of Nur77, with demonstrated beneficial effects on vascular cells both in vitro and in vivo [17]
Summary
Drug-eluting stents (DES) have dramatically reduced restenosis rates compared to bare metal stents and are widely used in coronary artery angioplasty. 6-Mercaptopurine (6-MP) is a drug with demonstrated cell-type specific effects on vascular cells both in vitro and in vivo, inhibiting proliferation of SMCs while promoting survival of endothelial cells. We demonstrated that DES locally releasing 6-MP during 4 weeks reduced in-stent stenosis by inhibiting SMC proliferation and reducing inflammation, without negatively affecting endothelialization of the stent surface. Stents loaded with a drug having a cell-type specific mechanism of action may effectively inhibit SMC proliferation and reduce restenosis without negatively interfering in the process of re-endothelialization of the stented artery segment, giving rise to safer stents and lower risk of the occurrence of thrombotic events. Nur is involved in differentiation of bone marrow-derived patrolling monocytes and reduces the inflammatory response of macrophages [12,13,14] Together, these functions protect against neointima formation and atherosclerosis in vivo in mouse models [15, 16]. Stents were implanted in porcine coronary arteries and the stented vessels were evaluated after 3 months
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