College of Pharmacy, Kinjo Gakuin University, Moriyama, Nagoya 463–8521, Japan.
Biol Pharm Bull. 2011;34(3):335-42. doi: 10.1248/bpb.34.335.
The protective effects of cyclic dipeptides in alcoholic beverages were investigated in the perfused guinea-pig hearts subjected to ischemia and reperfusion. Subsequently, in order to determine the importance of cyclic dipeptide structure, the effects of cyclo(L-Leu-L-Tyr) (cLY) were compared with those of the newly synthesized non-cyclic dipeptides, L-Leu-L-Tyr (LY) and L-Tyr-L-Leu (YL). After reperfusion, pressure recovery (%) in the left ventricle reached a peak of over 90% in the presence of cLY (10(-6) M and 10(-5) M) (control: 22.9%). The recovery by LY and YL was significantly lower than that by cLY, and ATP levels simultaneously monitored using (31)P-NMR were already lower during the ischemic end period than those observed with cLY treatment. In perfused mitochondrial preparations, cLY significantly inhibited mitochondrial Ca(2+) (Ca(2+)) elevation in a similar way to that of the mitochondrial permeability transition pore (MPTP) inhibitor cyclosporin A. In vitro electron paramagnetic resonance (EPR) revealed that the active oxygen radicals quenching activity of cLY was greater than those of non-cyclic dipeptides. cLY inhibited caspase-3-induced apoptosis. The cyclic dipeptide structure inhibits opening of the MPTP by preventing Ca(2+) overload-induced apoptosis related to mitochondrial active oxygen radical accumulation in ischemia-reperfusion hearts.
在缺血再灌注的灌流豚鼠心脏中研究了环状二肽在酒精饮料中的保护作用。随后，为了确定环状二肽结构的重要性，比较了环（L-亮氨酰-L-酪氨酰）（cLY）与新合成的非环状二肽 L-亮氨酰-L-酪氨酰（LY）和 L-酪氨酰-L-亮氨酰（YL）的作用。再灌注后，左心室压力恢复（%）在 cLY（10（-6）M 和 10（-5）M）存在下达到 90%以上（对照：22.9%）。LY 和 YL 的恢复明显低于 cLY，同时使用（31）P-NMR 监测的 ATP 水平在缺血末期已经低于 cLY 处理。在灌流线粒体制剂中，cLY 以类似于线粒体通透性转换孔（MPTP）抑制剂环孢菌素 A 的方式显著抑制线粒体 Ca（2+）（[Ca（2+）]（m））升高。体外电子顺磁共振（EPR）表明，cLY 的活性氧自由基淬灭活性大于非环状二肽。cLY 抑制半胱天冬酶-3 诱导的细胞凋亡。环状二肽结构通过防止 [Ca（2+）]（m）过载诱导与缺血再灌注心脏中线粒体活性氧自由基积累相关的细胞凋亡来抑制 MPTP 的开放。
