Maulik N, Watanabe M, Zu Y L, Huang C K, Cordis G A, Schley J A, Das D K
Department of Surgery, University of Connecticut School of Medicine, Farmington 06030-1110, USA.
FEBS Lett. 1996 Nov 4;396(2-3):233-7. doi: 10.1016/0014-5793(96)01109-x.
While much is known about the beneficial effects of myocardial stress adaptation, relatively less information is available about the adaptive mechanisms. To explore the signaling pathways of stress adaptation, isolated working rat hearts were divided into three groups. Group I was adapted to stress by conventional technique of repeated ischemia and reperfusion consisting of 5 min of ischemia followed by 10 min of reperfusion, repeated four times. Group II was treated with 100 microM of genistein, a tyrosine kinase inhibitor, followed by preconditioning as described for group I. The third group, perfused with buffer only for 60 min, served as control. All hearts were subjected to 30 min of ischemia followed by 30 min of reperfusion. The results of our study demonstrated better postischemic myocardial functions in the preconditioned hearts as evidenced by increased aortic flow, coronary flow, developed pressure and lesser amount of tissue injury as evidenced by the decreased creatine kinase release. The preconditioning effects were associated with enhancement of phospholipase D activity in the heart. The preconditioning effect was almost abolished by the genistein treatment which also prevented the enhancement of phospholipase D activities. Additionally, preconditioning of the rat hearts stimulated protein kinase C, MAP kinase, and MAPKAP kinase 2 activities which were inhibited by genistein. The results identifies for the first time tyrosine kinase-phospholipase D as potential signaling pathway for ischemic preconditioning, and implicates the involvement of multiple protein kinases in myocardial adaptation to ischemia.
虽然我们对心肌应激适应的有益作用了解很多，但关于其适应机制的信息相对较少。为了探索应激适应的信号通路，将离体工作大鼠心脏分为三组。第一组通过重复缺血再灌注的传统技术进行应激适应，即5分钟缺血后再灌注10分钟，重复4次。第二组先用100微摩尔的染料木黄酮（一种酪氨酸激酶抑制剂）处理，然后按照第一组的方法进行预处理。第三组仅用缓冲液灌注60分钟作为对照。所有心脏均经历30分钟缺血，随后再灌注30分钟。我们的研究结果表明，预处理的心脏缺血后心肌功能更好，表现为主动脉流量、冠状动脉流量增加，以及收缩压升高，并且组织损伤较少，表现为肌酸激酶释放减少。预处理效果与心脏中磷脂酶D活性增强有关。染料木黄酮处理几乎消除了预处理效果，同时也阻止了磷脂酶D活性的增强。此外，大鼠心脏的预处理刺激了蛋白激酶C、丝裂原活化蛋白激酶（MAP激酶）和丝裂原活化蛋白激酶相关激酶2的活性，而这些活性被染料木黄酮抑制。该结果首次确定酪氨酸激酶 - 磷脂酶D为缺血预处理的潜在信号通路，并表明多种蛋白激酶参与心肌对缺血的适应过程。
