Mitochondria are targets for geranylgeranylacetone-induced cardioprotection against ischemia-reperfusion in the rat heart
Mitochondria are targets for geranylgeranylacetone-induced cardioprotection against ischemia-reperfusion in the rat heart
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DOI：
10.1152/ajpheart.00493.2007
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发表时间：
2007-09-01
影响因子：
4.8
通讯作者：
Yoshimatsu, Hironobu
中科院分区：
文献类型：
--
作者：
Shinohara, Tetsuji;Takahashi, Naohiko;Yoshimatsu, Hironobu
研究表明，口服香叶基香叶基丙酮 (GGA)（一种抗溃疡药物）可诱导热休克蛋白 72 (HSP72) 的表达，并为大鼠心脏提供针对缺血再灌注的保护。然而，潜在的保护机制仍然未知。线粒体已被证明是热应激诱导的心脏保护的选择性靶标。因此，我们假设，由于线粒体内膜中假定的通道（线粒体 ATP 敏感钾 (mitoK(ATP)) 通道）打开，线粒体功能的保存可能参与 GGA 或热应激诱导的针对缺血再灌注的心脏保护作用。大鼠接受口服 GGA 或载体治疗。二十四小时后，分离每颗心脏并用 Langendorff 装置进行灌注。经过 GGA 处理的心脏显示出更好的功能恢复，并且在 20 分钟无流量缺血后的 30 分钟再灌注期间释放较少的肌酸激酶。同时灌注5-羟基癸酸（5-HD，100μM）或格列本脲（10μM）消除了GGA诱导的心脏保护作用。 GGA 还显示，在再灌注期结束时分离出保留的线粒体呼吸功能，该功能通过 5-HD 治疗而被消除。电子显微镜显示，GGA 可以防止缺血再灌注对线粒体结构的破坏。在培养的心肌细胞中，GGA 诱导 HSP72 表达，并减少对细胞的损伤，包括减少缺氧-复氧反应中的细胞凋亡。 5-HD治疗消除了GGA诱导的心脏保护作用，但不影响HSP72表达。我们的结果表明，由于 GGA 诱导的 HSP72 表达，保留的线粒体呼吸功能可能至少部分在针对缺血再灌注的心脏保护中发挥作用。这些过程可能涉及 mitoKATP 通道的打开。
It has been shown that orally administered geranylgeranylacetone (GGA), an anti-ulcer drug, induces expression of heat shock protein 72 (HSP72) and provides protection against ischemia-reperfusion in rat hearts. The underlying protective mechanisms, however, remain unknown. Mitochondria have been shown to be a selective target for heat stress-induced cardioprotection. Therefore, we hypothesized that preservation of mitochondrial function, owing to an opening of a putative channel in the inner mitochondrial membrane, the mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel, could be involved in GGA- or heat stress-induced cardioprotection against ischemia-reperfusion. Rats were treated with oral GGA or vehicle. Twenty-four hours later, each heart was isolated and perfused with a Langendorff apparatus. GGA-treated hearts showed better functional recovery, and less creatine kinase was released during a 30-min reperfusion period, after 20 min of no-flow ischemia. Concomitant perfusion with 5-hydroxydecanoate (5- HD, 100 mu M) or glibenclamide (10 mu M) abolished the GGA-induced cardioprotective effect. GGA also showed preserved mitochondrial respiratory function, isolated at the end of the reperfusion period, which was abolished with 5- HD treatment. GGA prevented destruction of the mitochondrial structure by ischemia-reperfusion, as shown by electron microscopy. In cultured cardiomyocytes, GGA induced HSP72 expression and resulted in less damage to cells, including less apoptosis in response to hypoxia-reoxygenation. Treatment with 5- HD abolished the GGA- induced cardioprotective effects but did not affect HSP72 expression. Our results indicate that preserved mitochondrial respiratory function, owing to GGA- induced HSP72 expression, may, at least in part, have a role in cardioprotection against ischemia-reperfusion. These processes may involve opening of the mitoKATP channel.