Jiangxi Provincial Key Laboratory of Molecular Medicine, Second Affiliated Hospital, Nanchang University, 1 Minde Road, Nanchang 330006, Jiangxi Province, PR China.
Int J Biochem Cell Biol. 2009 Nov;41(11):2315-22. doi: 10.1016/j.biocel.2009.05.021. Epub 2009 Jun 6.
Although anoxic preconditioning (APC) in the myocardium has been investigated for many years, its physiological mechanism is still not completely understood. Increasing evidence indicates that transiently increased resistance to ischemic damage following APC is dependent on de novo proteins synthesis. However, the key effector pathway(s) associated with APC still remains unclear. The proto-oncogene Pim kinase belongs to a serine/threoine protein kinase family, consists of Pim-1, Pim-2 and Pim-3 and has been implicated in stimulating cell growth and inhibiting cell apoptosis. Therefore we assumed that Pim-3 expression might be aberrantly induced in cardiomyocytes that were subjected to anoxia/reoxygenation (A/R) injury and that Pim-3 might also contribute to cardio-protection after APC. To address this hypothesis, we cloned a Pim-3 expression vector, transfected it into rat cardiomyocytes, and examined Pim-3 expression in rat cardiomyocytes that were subjected to A/R injury. Moreover, we studied the role of three major MAPK pathways, e.g. p38 MAPK, JNK, and ERK1/2, in order to evaluate the molecular mechanism underlying Pim-3 up-regulation and A/R induced cardiomyocyte injury. Our experiments showed that APC induced an up-regulation of Pim-3 and the transfection of Pim-3 gene into the cardiomyocytes attenuated A/R injury. The inhibition of p38 MAPK by SB203580 abolished both the Pim-3 up-regulation and the cardio-protection provided by APC. Overall, these results suggest that APC could act to protect the heart from A/R injury with cooperation from the proto-oncogene Pim-3; in addition, it up-regulates Pim-3 expression through a p38 MAPK signaling pathway.
虽然心肌缺氧预处理（APC）已经研究了很多年，但它的生理机制仍不完全清楚。越来越多的证据表明，APC 后短暂增加对缺血损伤的抵抗力依赖于新蛋白质的合成。然而，与 APC 相关的关键效应途径仍不清楚。原癌基因 Pim 激酶属于丝氨酸/苏氨酸蛋白激酶家族，由 Pim-1、Pim-2 和 Pim-3 组成，与刺激细胞生长和抑制细胞凋亡有关。因此，我们假设在经历缺氧/复氧（A/R）损伤的心肌细胞中，Pim-3 的表达可能异常增加，并且 Pim-3 也可能有助于 APC 后的心脏保护。为了验证这一假设，我们克隆了 Pim-3 表达载体，转染大鼠心肌细胞，并检测了 A/R 损伤后大鼠心肌细胞中 Pim-3 的表达。此外，我们研究了三种主要的 MAPK 途径（p38 MAPK、JNK 和 ERK1/2）的作用，以评估 Pim-3 上调和 A/R 诱导的心肌细胞损伤的分子机制。我们的实验表明，APC 诱导 Pim-3 的上调，并且将 Pim-3 基因转染到心肌细胞中可以减轻 A/R 损伤。p38 MAPK 的抑制剂 SB203580 消除了 APC 提供的 Pim-3 上调和心脏保护作用。总的来说，这些结果表明，APC 可以通过原癌基因 Pim-3 与心脏合作来保护心脏免受 A/R 损伤；此外，它通过 p38 MAPK 信号通路上调 Pim-3 的表达。
