Rapamycin confers preconditioning-like protection against ischemia-reperfusion injury in isolated mouse heart and cardiomyocytes
Rapamycin confers preconditioning-like protection against ischemia-reperfusion injury in isolated mouse heart and cardiomyocytes
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DOI：
10.1016/j.yjmcc.2006.04.014
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发表时间：
2006-08-01
影响因子：
5
通讯作者：
Kukreja, Rakesh C.
中科院分区：
文献类型：
--
作者：
Khan, Shakil A.;Salloum, Fadi;Kukreja, Rakesh C.
雷帕霉素（西罗莫司）是一种通过哺乳动物雷帕霉素靶蛋白（mTOR）信号抑制蛋白质合成的抗生素，被用作治疗器官排斥的免疫抑制剂。最近，雷帕霉素的抗生长特性已被用于心血管益处，因为雷帕霉素浸透支架可有效减少冠状动脉再狭窄。我们在这里报告了这种药物在保护缺血/再灌注（I/R）损伤中的新作用。用雷帕霉素（0.25 mg/kg， IP）或体积匹配的DMSO（雷帕霉素的溶剂）处理成年雄性ICR小鼠。在Langendorff模式下，心脏局部缺血20 min，再灌注30 min。缺血前10分钟给予线粒体K-ATP通道阻滞剂5-羟癸酸（5-HD, 100 μ M）。DMSO治疗组的梗死面积为28.2 +/- 1.3%，雷帕霉素治疗组的梗死面积为10.1 +/- 2.8%（减少64%，P < 0.001）。5-HD阻断了保护作用（梗死面积32.2 +/- 1.8%，与雷帕霉素相比P < 0.001）。雷帕霉素的梗死限制作用与心室功能的改善恢复无关。我们进一步研究了雷帕霉素在模拟缺血和再氧化成人心肌细胞中对坏死和凋亡的保护作用。25-100 nM剂量的雷帕霉素处理心肌细胞，可显著降低台盼蓝阳性坏死细胞和tunel阳性凋亡核，支持药物对完整心脏的保护作用。这些数据表明，雷帕霉素通过打开线粒体K-ATP通道诱导了有效的预处理样心肌梗死效应。我们认为雷帕霉素可能是一种新的治疗策略，可以限制心脏I/R损伤后的梗死、细胞凋亡和重塑。(c) 2006爱思唯尔系列。版权所有。
Rapamycin (sirolimus) is an antibiotic that inhibits protein synthesis through mammalian target of rapamycin (mTOR) signaling and is used as an immunosuppressant in the treatment of organ rejection in transplant recipients. Recently, the antigrowth properties of rapamycin have been utilized for cardiovascular benefit as stents impregnated with rapamycin effectively reduce coronary restenosis. We report here a novel role of this drug in protection against ischemia/reperfasion (I/R) injury. Adult male ICR mice were treated with raparrycin (0.25 mg/kg, IP) or volume-matched DMSO (solvent for rapamycin). The hearts were subjected to 20 min of global ischemia and 30 min of reperfusion in Langendorff mode. The blocker of mitochondrial K-ATP channel, 5-hydroxydecanoate (5-HD, 100 mu M) was given 10 min before ischemia. Infarct size in the DMSO treated group was 28.2 +/- 1.3% and was reduced to 10.1 +/- 2.8% in the rapamycin-treated mice (64% decrease, P < 0.001). 5-HD blocked the protective effect (infarct area 32.2 +/- 1.8%, P < 0.001 vs. rapamycin). The infarct limiting effect of rapamycin was not associated with improved recovery of ventricular function. We further examined the effect of rapamycin in protection against necrosis and apoptosis in adult cardiomyocytes subjected to simulated ischemia and reoxygenation. Myocytes treated with rapamycin in doses from 25-100 nM demonstrated significantly lower trypan blue-positive necrotic cells and TUNEL-positive apoptotic nuclei, supporting the protective role of drug in the intact heart. These data suggest that rapamycin induces potent preconditioning-like effect against myocardial infarction through opening of mitochondrial K-ATP channels. We propose that rapamycin may be a novel therapeutic strategy to limit infarction, apoptosis, and remodeling following I/R injury in the heart. (c) 2006 Elsevier line. All rights reserved.