Gao Hao-Kao, Yin Zhong, Zhou Ning, Feng Xu-Yang, Gao Feng, Wang Hai-Chang
Department of Cardiology, Xi Jing Hospital, Fourth Military Medical University; Xi'an, China.
J Cardiovasc Pharmacol. 2008 Sep;52(3):286-92. doi: 10.1097/FJC.0b013e318186a84d.
Glycogen synthase kinase (GSK)-3beta inhibitors play an anti-inflammatory role in several inflammatory diseases. Recent studies have demonstrated that GSK-3beta inhibitors protect against myocardial ischemia-reperfusion injury. However, the precise mechanisms remain unclear. We aimed to investigate the roles of inflammation and apoptosis induced by ischemia-reperfusion in the cardioprotection by GSK-3beta inhibitor 4-benzyl-2-methyl-1, 2, 4-thiadiazolidine-3, 5-dione (TDZD-8). Anaesthetized Sprague-Dawley rats underwent an open-chest procedure involving 30 min of myocardial ischemia and 6 h of reperfusion with or without TDZD-8 given at reperfusion. TDZD-8 reduced myocardial infarct size by nearly 43% (P < 0.05 vs. myocardial ischemia-reperfusion) and attenuated myeloperoxidase activity (21.80 +/- 1.07 U/100 mg tissue. vs. myocardial ischemia-reperfusion group, P < 0.05). Administration of TDZD-8 significantly suppressed nuclear factor kappa B (NF-kappaB) and p38 MAPK activation (P < 0.05 vs. myocardial ischemia-reperfusion) and the concentrations of the myocardial-derived cytokines tumor necrosis factor-alpha (TNF-alpha, 107.40 +/- 7.34 pg/mg protein vs. myocardial ischemia-reperfusion group, P < 0.05) and interleukin-6 (IL-6, 29.28 +/- 6.3 pg/mg protein vs. myocardial ischemia-reperfusion group, P < 0.05). Treatment with TDZD-8 also inhibited myocardial cell apoptosis compared with the myocardial ischemia-reperfusion group (12 +/- 1% vs. 22 +/- 2%, P < 0.05). Therefore, blocking this protein kinase activity may be a novel approach to the treatment of this condition, which is characterized by inflammation and apoptosis.
糖原合酶激酶（GSK）-3β抑制剂在多种炎症性疾病中发挥抗炎作用。最近的研究表明，GSK-3β抑制剂可预防心肌缺血-再灌注损伤。然而，确切机制仍不清楚。我们旨在研究缺血-再灌注诱导的炎症和凋亡在GSK-3β抑制剂4-苄基-2-甲基-1,2,4-噻二唑烷-3,5-二酮（TDZD-8）心脏保护作用中的作用。对麻醉的Sprague-Dawley大鼠进行开胸手术，使其经历30分钟的心肌缺血和6小时的再灌注，再灌注时给予或不给予TDZD-8。TDZD-8使心肌梗死面积减少近43%（与心肌缺血-再灌注组相比，P<0.05），并减弱髓过氧化物酶活性（21.80±1.07 U/100 mg组织，与心肌缺血-再灌注组相比，P<0.05）。给予TDZD-8可显著抑制核因子κB（NF-κB）和p38丝裂原活化蛋白激酶（MAPK）的激活（与心肌缺血-再灌注组相比，P<0.05）以及心肌源性细胞因子肿瘤坏死因子-α（TNF-α，107.40±7.34 pg/mg蛋白，与心肌缺血-再灌注组相比，P<0.05）和白细胞介素-6（IL-6，29.28±6.3 pg/mg蛋白，与心肌缺血-再灌注组相比，P<0.05）的浓度。与心肌缺血-再灌注组相比，TDZD-8治疗还抑制了心肌细胞凋亡（12±1%对22±2%，P<0.05）。因此，阻断这种蛋白激酶活性可能是治疗这种以炎症和凋亡为特征疾病的新方法。
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