Chibana Hidetoshi, Kajimoto Hidemi, Ueno Takafumi, Yokoyama Shinji, Sasaki Ken-Ichiro, Ohtsuka Masanori, Koiwaya Hiroshi, Nakayoshi Takaharu, Mitsutake Yoshiaki, Itaya Naoki, Sasaki Masahiro, Fukumoto Yoshihiro
Division of Cardio-Vascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan.
Heart Vessels. 2017 Jul;32(7):823-832. doi: 10.1007/s00380-017-0947-x. Epub 2017 Jan 23.
Implantation of mammalian target of rapamycin (mTOR)-inhibitor drug-eluting stents (DESs) impairs coronary endothelial function. There are no known non-invasive biomarkers of coronary endothelial dysfunction. We aimed to assess the association between serum interleukin-1beta (IL-1β) and coronary endothelial dysfunction in patients with mTOR-inhibitor DES implantation and to investigate the association between the mTOR pathway and IL-1β. We enrolled 35 patients who had implanted DESs for coronary artery disease. At a 10-month follow-up, peripheral venous blood samples were collected to measure IL-1β levels. Coronary endothelial dysfunction was evaluated by intracoronary infusion of incremental doses of acetylcholine. Serum IL-1β levels were significantly associated with the magnitude of vasoconstriction to acetylcholine at the segment distal (P < 0.05) but not proximal to the stent. Serum IL-1β levels were positively correlated with stent length (P < 0.05). To examine the direct effects of mTOR inhibition on IL-1β release, sirolimus was incubated in cultured human umbilical vein endothelial cells (HUVECs) or coronary artery smooth muscle cells (CASMCs). Sirolimus directly increased IL-1β mRNA expression (P < 0.01) and enhanced IL-1β release into the culture media (P < 0.01) in CASMCs, but not in HUVECs. Inhibition of mTOR triggers IL-1β release through transcriptional activation in CASMCs. Serum IL-1β levels are a potential biomarker for mTOR-inhibitor DES-associated coronary endothelial dysfunction.
雷帕霉素哺乳动物靶点（mTOR）抑制剂药物洗脱支架（DESs）的植入会损害冠状动脉内皮功能。目前尚无已知的冠状动脉内皮功能障碍的非侵入性生物标志物。我们旨在评估mTOR抑制剂DES植入患者血清白细胞介素-1β（IL-1β）与冠状动脉内皮功能障碍之间的关联，并研究mTOR通路与IL-1β之间的关联。我们纳入了35例因冠状动脉疾病植入DESs的患者。在10个月的随访中，采集外周静脉血样本以测量IL-1β水平。通过冠状动脉内递增剂量注射乙酰胆碱来评估冠状动脉内皮功能障碍。血清IL-1β水平与支架远端节段对乙酰胆碱的血管收缩幅度显著相关（P < 0.05），但与支架近端无关。血清IL-1β水平与支架长度呈正相关（P < 0.05）。为了研究mTOR抑制对IL-1β释放的直接影响，将西罗莫司与人脐静脉内皮细胞（HUVECs）或冠状动脉平滑肌细胞（CASMCs）共同培养。西罗莫司直接增加了CASMCs中IL-1β mRNA的表达（P < 0.01），并增强了IL-1β向培养基中的释放（P < 0.01），但在HUVECs中未观察到这种现象。mTOR的抑制通过转录激活触发了CASMCs中IL-1β的释放。血清IL-1β水平是mTOR抑制剂DES相关冠状动脉内皮功能障碍的潜在生物标志物。
