Delayed reendothelialization with rapamycin is rescued by the addition of nicorandil in balloon-injured rat carotid arteries
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Ying Qian Zhang1, Feng Tian1,*, Jin Song Chen2,1, Yun Dai Chen1, Ying Zhou3,1, Bo Li1, Qiang Ma1, Ying Zhang1
1Department of Cardiology, Chinese PLA General Hospital, Beijing, China
2Department of Cardiology, Chinese PLA 175th Hospital, Fujian, China
3VIP Medical Service Department, Beijing Shijitan Hospital, Beijing, China
*Co-first author of this article
Keywords: nicorandil, rapamycin, xanthine oxidase, endothelium, angioplasty
Received: January 07, 2016 Accepted: September 24, 2016 Published: October 04, 2016
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.
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