Cho Janghyun, Won Kyungheon, Wu DunLi, Soong Yi, Liu Shaoyi, Szeto Hazel H, Hong Mun K
Department of Medicine, St Carollo Hospital, Suncheon City, Seoul Medical Center, Seoul, Korea, and Department of Pharmacology, Weill Cornell Medical College, New York, New York 10025, USA.
Coron Artery Dis. 2007 May;18(3):215-20. doi: 10.1097/01.mca.0000236285.71683.b6.
Previously, we demonstrated that a novel opiate peptide, 2',6'-dimethyl-tyrosine-D-Arg-Phe-Lys-NH2, provided cardioprotection against myocardial stunning in vivo. We subsequently showed that this peptide targeted mitochondria and can scavenge reactive oxygen species. The objective of this study was to determine the role of opioid versus antioxidant activity in cardioprotection.
We compared two mitochondria-targeted peptide analogs that lacked opioid activity: SS-31 (D-Arg-2',6'-dimethyl-tyrosine-Lys-Phe-NH2) and SS-20 (Phe-D-Arg-Phe-Lys-NH2). They differ in that only SS-31 has scavenging ability. Rats (n=8/group) were randomized to SS-31, SS-20 or placebo. The drugs (3 mg/kg) or saline was administered intraperitoneally 30 min before ligation of the left anterior descending artery for 60 min, and another dose given intraperitoneally 5 min before reperfusion for 60 min. Study endpoints included myocardial infarct size, cardiac arrhythmia and myocardial lipid peroxidation.
The area at risk was similar among the groups. The infarct area/area at risk, however, was significantly smaller in the treatment groups (53.9+/-1.1% in SS-31 group, 47.1+/-1.4% in SS-20 group, versus 59.9+/-1% in the controls, P<0.01). Lipid peroxidation was significantly reduced by both SS-31 and SS-20 treatment. Arrhythmia occurred only during the early period of coronary occlusion and was less frequent and less severe in the peptide treatment groups than in the controls (Lambeth score 5 points, 3 points, versus 13 points in the controls, P<0.05).
This study shows that pretreatment with both SS-31 and SS-20 significantly reduced myocardial lipid peroxidation and infarct size in ischemia-reperfusion injury, and suggests that the cardioprotective properties of 2',6'-dimethyl-tyrosine-D-Arg-Phe-Lys-NH2 was primarily mediated by its antioxidant properties. As SS-20 does not scavenge reactive oxygen species, it most likely reduces reactive oxygen species production during ischemia-reperfusion.
此前，我们证明了一种新型阿片肽2'，6'-二甲基酪氨酸-D-精氨酸-苯丙氨酸-赖氨酸-NH2在体内对心肌顿抑具有心脏保护作用。随后我们发现该肽靶向线粒体并能清除活性氧。本研究的目的是确定阿片样物质活性与抗氧化活性在心脏保护中的作用。
我们比较了两种缺乏阿片样物质活性的线粒体靶向肽类似物：SS-31（D-精氨酸-2'，6'-二甲基酪氨酸-赖氨酸-苯丙氨酸-NH2）和SS-20（苯丙氨酸-D-精氨酸-苯丙氨酸-赖氨酸-NH2）。它们的不同之处在于只有SS-31具有清除能力。将大鼠（每组n = 8）随机分为SS-31组、SS-20组或安慰剂组。在结扎左前降支60分钟前30分钟腹腔注射药物（3mg/kg）或生理盐水，再灌注60分钟前5分钟腹腔注射另一剂。研究终点包括心肌梗死面积、心律失常和心肌脂质过氧化。
各组之间的危险区域相似。然而，治疗组的梗死面积/危险区域明显较小（SS-31组为53.9±1.1%，SS-20组为47.1±1.4%，而对照组为59.9±1%，P<0.01）。SS-31和SS-20治疗均显著降低脂质过氧化。心律失常仅发生在冠状动脉闭塞早期，肽治疗组的发生率和严重程度均低于对照组（兰贝斯评分分别为5分、3分，而对照组为13分，P<0.05）。
本研究表明，SS-31和SS-20预处理均能显著降低缺血再灌注损伤中的心肌脂质过氧化和梗死面积，并提示2'，6'-二甲基酪氨酸-D-精氨酸-苯丙氨酸-赖氨酸-NH2的心脏保护特性主要由其抗氧化特性介导。由于SS-20不能清除活性氧，它很可能减少缺血再灌注期间活性氧的产生。
