Khan Shakil, Salloum Fadi, Das Anindita, Xi Lei, Vetrovec George W, Kukreja Rakesh C
Department of Internal Medicine, Division of Cardiology, Virginia Commonwealth University Medical Center, Richmond, 23298, USA.
J Mol Cell Cardiol. 2006 Aug;41(2):256-64. doi: 10.1016/j.yjmcc.2006.04.014.
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/reperfusion (I/R) injury. Adult male ICR mice were treated with rapamycin (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 KATP channel, 5-hydroxydecanoate (5-HD, 100 microM) 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 KATP channels. We propose that rapamycin may be a novel therapeutic strategy to limit infarction, apoptosis, and remodeling following I/R injury in the heart.
雷帕霉素（西罗莫司）是一种抗生素，它通过哺乳动物雷帕霉素靶蛋白（mTOR）信号传导抑制蛋白质合成，并作为免疫抑制剂用于治疗移植受者的器官排斥反应。最近，雷帕霉素的抗生长特性已被用于心血管益处，因为浸渍有雷帕霉素的支架可有效减少冠状动脉再狭窄。我们在此报告该药物在预防缺血/再灌注（I/R）损伤中的新作用。成年雄性ICR小鼠用雷帕霉素（0.25mg/kg，腹腔注射）或体积匹配的二甲基亚砜（DMSO，雷帕霉素的溶剂）处理。心脏在Langendorff模式下进行20分钟的全心缺血和30分钟的再灌注。在缺血前10分钟给予线粒体KATP通道阻滞剂5-羟基癸酸（5-HD，100μM）。DMSO处理组的梗死面积为28.2±1.3%，而雷帕霉素处理的小鼠梗死面积减少至10.1±2.8%（减少64%，P<0.001）。5-HD阻断了这种保护作用（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对模拟缺血和复氧的成年心肌细胞坏死和凋亡的保护作用。用25-100 nM剂量的雷帕霉素处理的心肌细胞显示，台盼蓝阳性坏死细胞和TUNEL阳性凋亡核明显减少，这支持了该药物在完整心脏中的保护作用。这些数据表明，雷帕霉素通过打开线粒体KATP通道诱导对心肌梗死的强效预处理样作用。我们提出，雷帕霉素可能是一种限制心脏I/R损伤后梗死、凋亡和重塑的新治疗策略。
