Button Laura, Mireylees Stewart E, Germack Renee, Dickenson John M
School of Biomedical and Natural Sciences, Nottingham Trent University, Clifton Lane, Nottingham NG11 8NS, UK.
Exp Physiol. 2005 Sep;90(5):747-54. doi: 10.1113/expphysiol.2005.030635. Epub 2005 Jun 17.
Mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase 1 and 2 (ERK1/2) and phosphatidylinositol 3-kinase (PI3-kinase)/protein kinase B (PKB; also known as Akt) are important antiapoptotic signalling pathways which have recently been implicated in cardioprotection. However, at present the involvement of ERK1/2 and PI3-kinase/PKB in adenosine receptor-mediated cardioprotection is poorly understood. In this study we used isolated rat right ventricular strips, contracted by electrical-field stimulation, in order to investigate the role of ERK1/2 and PI3-kinase/PKB in adenosine receptor-induced cardioprotection. Ventricle strips were pretreated for 2 min with the agonists adenosine (non-selective), CPA (A1 selective), CGS 21680 (A2A selective) and Cl-IB-MECA (A3 selective) before 30 min hypoxia followed by 30 min reoxygenation. Each agonist significantly improved posthypoxic percentage contraction recovery compared to control strips. Similarly hypoxic preconditioning (10 min hypoxia followed by 20 min reoxygenation) significantly improved posthypoxic percentage contraction recovery compared to non-preconditioned strips. The selective adenosine receptor antagonists DPCPX (A1), ZM 241385 (A2A) and MRS 1220 (A3) attenuated cardioprotection induced by CPA, CGS 21680 and Cl-IB-MECA, respectively. Pre-incubation (30 min) of ventricle strips with the MEK1 inhibitor PD 98059 (50 microM) or the PI3-kinase inhibitor wortmannin (100 nM) significantly reduced posthypoxic percentage contraction recovery induced by hypoxic preconditioning. In contrast, PD 98059 and wortmannin had no significant effect on cardioprotection induced by CPA, Cl-IB-MECA or CGS 21680. Overall these data indicate that although selective A1, A2A and A3 adenosine receptor agonists induce preconditioning in rat right ventricular strips the effects are independent of ERK1/2- and PI3-kinase-dependent pathways. In contrast ERK1/2 and PI3-kinase-dependent pathways do appear to be involved in early hypoxic preconditioning.
丝裂原活化蛋白激酶激酶（MEK）/细胞外信号调节激酶1和2（ERK1/2）以及磷脂酰肌醇3激酶（PI3激酶）/蛋白激酶B（PKB；也称为Akt）是重要的抗凋亡信号通路，最近已被证明与心脏保护有关。然而，目前ERK1/2和PI3激酶/PKB在腺苷受体介导的心脏保护中的作用尚不清楚。在本研究中，我们使用电场刺激收缩的离体大鼠右心室条带，以研究ERK1/2和PI3激酶/PKB在腺苷受体诱导的心脏保护中的作用。在30分钟缺氧后再进行30分钟复氧之前，用激动剂腺苷（非选择性）、CPA（A1选择性）、CGS 21680（A2A选择性）和Cl-IB-MECA（A3选择性）对心室条带进行2分钟预处理。与对照条带相比，每种激动剂均显著提高了缺氧后收缩恢复百分比。同样，与未预处理的条带相比，缺氧预处理（10分钟缺氧后再进行20分钟复氧）显著提高了缺氧后收缩恢复百分比。选择性腺苷受体拮抗剂DPCPX（A1）、ZM 241385（A2A）和MRS 1220（A3）分别减弱了CPA、CGS 21680和Cl-IB-MECA诱导的心脏保护作用。用MEK1抑制剂PD 98059（50微摩尔）或PI3激酶抑制剂渥曼青霉素（100纳摩尔）对心室条带进行预孵育（30分钟），显著降低了缺氧预处理诱导的缺氧后收缩恢复百分比。相反，PD 98059和渥曼青霉素对CPA、Cl-IB-MECA或CGS 21680诱导的心脏保护作用无显著影响。总体而言，这些数据表明，尽管选择性A1、A2A和A3腺苷受体激动剂在大鼠右心室条带中诱导预处理，但其作用独立于ERK1/2和PI3激酶依赖性途径。相反，ERK1/2和PI3激酶依赖性途径似乎确实参与了早期缺氧预处理。
