Reperfusion-induced translocation of δPKC to cardiac mitochondria prevents pyruvate dehydrogenase reactivation
Reperfusion-induced translocation of δPKC to cardiac mitochondria prevents pyruvate dehydrogenase reactivation
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DOI：
10.1161/01.res.0000173896.32522.6e
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发表时间：
2005-07-08
影响因子：
20.1
通讯作者：
Szweda, LI
中科院分区：
文献类型：
--
作者：
Churchill, EN;Murriel, CL;Szweda, LI
心肌缺血和再灌注与线粒体丙酮酸脱氢酶（PDH）活性的丧失有关。PDH活性的药理学刺激改善再灌注期间收缩功能的恢复。因此，再灌注过程中控制抑制和再激活的PDH的信号机制进行了研究。使用离体大鼠心脏模型，我们观察到缺血诱导的HH抑制，再灌注时仅部分恢复明显。在再灌注过程中发生的氧化还原敏感的δ-亚型蛋白激酶C（PKC）的线粒体易位。抑制该过程导致PDH活性完全恢复。在常氧灌注期间输注delta PKC激活剂H2 O2，以模拟心脏再灌注的一个方面，导致PDH活性的丧失，这在很大程度上归因于delta PKC向线粒体的易位。有证据表明，再灌注诱导的δ PKC易位与PDH α E1亚基的磷酸化有关。一个潜在的机制是在体外数据表明，δ PKC特异性相互作用和磷酸化丙酮酸脱氢酶激酶（PDK）2。重要的是，这导致PDK 2的活化，PDK 2是一种能够磷酸化和抑制PDH的酶。因此，在再灌注过程中，δ PKC向线粒体的易位可能导致PDK 2的激活和PDH的磷酸化依赖性抑制。
Cardiac ischemia and reperfusion are associated with loss in the activity of the mitochondrial enzyme pyruvate dehydrogenase ( PDH). Pharmacological stimulation of PDH activity improves recovery in contractile function during reperfusion. Signaling mechanisms that control inhibition and reactivation of PDH during reperfusion were therefore investigated. Using an isolated rat heart model, we observed ischemia-induced PDH inhibition with only partial recovery evident on reperfusion. Translocation of the redox-sensitive delta-isoform of protein kinase C (PKC) to the mitochondria occurred during reperfusion. Inhibition of this process resulted in full recovery of PDH activity. Infusion of the delta PKC activator H2O2 during normoxic perfusion, to mimic one aspect of cardiac reperfusion, resulted in loss in PDH activity that was largely attributable to translocation of delta PKC to the mitochondria. Evidence indicates that reperfusion-induced translocation of delta PKC is associated with phosphorylation of the alpha E1 subunit of PDH. A potential mechanism is provided by in vitro data demonstrating that delta PKC specifically interacts with and phosphorylates pyruvate dehydrogenase kinase (PDK)2. Importantly, this results in activation of PDK2, an enzyme capable of phosphorylating and inhibiting PDH. Thus, translocation of delta PKC to the mitochondria during reperfusion likely results in activation of PDK2 and phosphorylation-dependent inhibition of PDH.