Department of Biochemistry and the Bristol Heart Institute, University of Bristol, University Walk, Bristol BS8 1TD, UK.
Cardiovasc Res. 2010 Nov 1;88(2):324-33. doi: 10.1093/cvr/cvq190. Epub 2010 Jun 16.
Temperature preconditioning (TP) provides very powerful protection against ischaemia/reperfusion. Understanding the signalling pathways involved may enable the development of effective pharmacological cardioprotection. We investigated the interrelationship between activation of protein kinase A (PKA) and protein kinase C (PKC) in the signalling mechanisms of TP and developed a potent pharmacological intervention based on this mechanism.
Isolated rat hearts were subjected to TP, 30 min global ischaemia, and 60 min reperfusion. Other control and TP hearts were perfused with either sotalol (β-adrenergic blocker) or H-89 (PKA inhibitor). Some hearts were pre-treated with either isoproterenol (β-adrenergic agonist) or adenosine (PKC activator) that were given alone, simultaneously, or sequentially. Pre-treatment with isoproterenol, adenosine, and the consecutive isoproterenol/adenosine treatment was also combined with the PKC inhibitor chelerythrine. Cardioprotection was evaluated by haemodynamic function recovery, lactate dehydrogenase release, measurement of mitochondrial permeability transition pore opening, and protein carbonylation during reperfusion. Cyclic AMP and PKA activity were increased in TP hearts. H-89 and sotalol blocked the cardioprotective effect of TP and TP-induced PKC activation. Isoproterenol, adenosine, and the consecutive treatment increased PKC activity during pre-ischaemia. Isoproterenol significantly reduced myocardial glycogen content. Isoproterenol and adenosine, alone or simultaneously, protected hearts but the consecutive treatment gave the highest protection. Cardioprotective effects of adenosine were completely blocked by chelerythrine but those of the consecutive treatment only attenuated.
The signal transduction pathway of TP involves PKA activation that precedes PKC activation. Pharmacologically induced consecutive PKA/PKC activation mimics TP and induces extremely potent cardioprotection.
温度预处理（TP）对缺血/再灌注具有非常强大的保护作用。了解涉及的信号通路可能使开发有效的药物心脏保护成为可能。我们研究了蛋白激酶 A（PKA）和蛋白激酶 C（PKC）的激活在 TP 的信号转导机制中的相互关系，并在此基础上开发了一种有效的药物干预方法。
分离的大鼠心脏进行 TP、30 分钟全缺血和 60 分钟再灌注。其他对照和 TP 心脏用索他洛尔（β-肾上腺素能阻滞剂）或 H-89（PKA 抑制剂）灌注。一些心脏用单独、同时或顺序给予异丙肾上腺素（β-肾上腺素能激动剂）或腺苷（PKC 激活剂）预处理。异丙肾上腺素、腺苷和连续异丙肾上腺素/腺苷处理也与 PKC 抑制剂 Chelerythrine 联合使用。通过再灌注期间的血流动力学功能恢复、乳酸脱氢酶释放、测量线粒体通透性转换孔开放和蛋白质羰基化来评估心脏保护作用。TP 心脏中环腺苷酸（cAMP）和 PKA 活性增加。H-89 和索他洛尔阻断了 TP 的心脏保护作用和 TP 诱导的 PKC 激活。异丙肾上腺素、腺苷和连续处理在缺血前增加了 PKC 活性。异丙肾上腺素显著降低心肌糖原含量。异丙肾上腺素和腺苷单独或同时保护心脏，但连续处理提供了最高的保护。Chelerythrine 完全阻断了腺苷的心脏保护作用，但连续处理仅减弱了其作用。
TP 的信号转导途径涉及 PKA 的激活，随后是 PKC 的激活。药理学诱导的连续 PKA/PKC 激活模拟了 TP，并诱导了极其强大的心脏保护作用。
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