Abstract

Rapamycin is an immunosuppressive agent that is added to drug eluting stents. It prevents restenosis, but it also impairs reendothelialization. Nicorandil is a hybrid agent with adenosine triphosphated (ATP)-sensitive K+ (KATP) channel opener and nitrate properties. It prevents oxidative stress and cell apoptosis induced by rapamycin in endothelial cells in vitro. However, whether nicorandil promotes reendothelialization after angioplasty delayed by rapamycin remains to be determined. Balloon injury model was established in SD rats. Nicorandil increased reendothelialization impaired by rapamycin, and it decreased xanthine oxidase (XO)-generated reactive oxygen species (ROS) induced by rapamycin. In addition, eNOS expression inhibited by rapamycin was increased by nicorandil in vivo. In vitro, rapamycin-impeded cardiac microvascular endothelial cells (CMECs) migration, proliferation and rapamycin-induced ROS production were reversed by nicorandil. Knockdown of XO partially inhibited rapamycin-induced ROS production and cell apoptosis in CMECs, and it promoted CMECs migration and proliferation suppressed by rapamycin. Knockdown of Akt partially prevents eNOS upregulation promoted by nicorandil. The beneficial effect of nicorandil is exhibited by inhibiting XO and up-regulating Akt pathway. Nicorandil combined with rapamycin in effect rescue the deficiencies of rapamycin alone in arterial healing after angioplasty.

Highlights

  • Drug eluting stents (DESs) are developed for preventing restenosis after percutaneous coronary intervention (PCI)

  • PECAM-1(CD31) positive cells in lumen surface showed a partial restoration of the endothelial cell monolayer in balloon injury (BI) group, and rapamycin decreased this restoration

  • The effects of nicorandil and rapamycin on intimal hyperplasia were evaluated. 14 days after balloon injury, intimal hyperplasia developed in BI group, whereas it was suppressed in rapamycin group (Figure 1D)

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Summary

Introduction

Drug eluting stents (DESs) are developed for preventing restenosis after percutaneous coronary intervention (PCI). Clinical studies suggest that DESs delay reendothelialization, and DESs appear to be accompanied by a higher prevalence of stent thrombosis [1]. Rapamycin is an immunosuppressive agent that is added to DESs. Rapamycin is an immunosuppressive agent that is added to DESs It inhibits vascular smooth muscle cell proliferation and migration to prevent restenosis [2]. It induces autophagy and apoptosis in endothelial cells [3], increases oxidative stress [4], and suppresses healing of the endothelium [3]. Preclinical studies revealed that nicorandil attenuates endothelial VACM1 expression in diabetic rats [7], prevents rapamycininduced production of reactive oxygen species (ROS) [8], promotes eNOS expression [9], and inhibits endothelial cells apoptosis [10]. Nicorandil may promote early phase of reendothelialization that is delayed by rapamycin

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