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蛋白激酶A和Epac同时激活与单独激活的功能及心脏保护作用

Functional and cardioprotective effects of simultaneous and individual activation of protein kinase A and Epac.

作者信息

Khaliulin Igor, Bond Mark, James Andrew F, Dyar Zara, Amini Raheleh, Johnson Jason L, Suleiman M-Saadeh

机构信息

School of Clinical Sciences and Bristol Cardiovascular, University of Bristol, Bristol, UK.

出版信息

Br J Pharmacol. 2017 Mar;174(6):438-453. doi: 10.1111/bph.13709. Epub 2017 Feb 14.

DOI:10.1111/bph.13709
PMID:28071786
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5323515/
Abstract

BACKGROUND AND PURPOSE

Myocardial cAMP elevation confers cardioprotection against ischaemia/reperfusion (I/R) injury. cAMP activates two independent signalling pathways, PKA and Epac. This study investigated the cardiac effects of activating PKA and/or Epac and their involvement in cardioprotection against I/R.

EXPERIMENTAL APPROACH

Hearts from male rats were used either for determination of PKA and PKC activation or perfused in the Langendorff mode for either cardiomyocyte isolation or used to monitor functional activity at basal levels and after 30 min global ischaemia and 2 h reperfusion. Functional recovery and myocardial injury during reperfusion (LDH release and infarct size) were evaluated. Activation of PKA and/or Epac in perfused hearts was induced using cell permeable cAMP analogues in the presence or absence of inhibitors of PKA, Epac and PKC. H9C2 cells and cardiomyocytes were used to assess activation of Epac and effect on Ca transients.

KEY RESULTS

Selective activation of either PKA or Epac was found to trigger a positive inotropic effect, which was considerably enhanced when both pathways were simultaneously activated. Only combined activation of PKA and Epac induced marked cardioprotection against I/R injury. This was accompanied by PKCε activation and repressed by inhibitors of PKA, Epac or PKC.

CONCLUSION AND IMPLICATIONS

Simultaneous activation of both PKA and Epac induces an additive inotropic effect and confers optimal and marked cardioprotection against I/R injury. The latter effect is mediated by PKCε activation. This work has introduced a new therapeutic approach and targets to protect the heart against cardiac insults.

摘要

背景与目的

心肌中环磷酸腺苷（cAMP）水平升高可赋予心脏对缺血/再灌注（I/R）损伤的保护作用。cAMP激活两条独立的信号通路，即蛋白激酶A（PKA）和交换蛋白直接激活剂（Epac）。本研究调查了激活PKA和/或Epac对心脏的影响及其在抗I/R心脏保护中的作用。

实验方法

使用雄性大鼠的心脏，要么用于测定PKA和蛋白激酶C（PKC）的激活情况，要么采用Langendorff模式灌注，用于分离心肌细胞，或者用于监测基础水平以及30分钟全心缺血和2小时再灌注后的功能活性。评估再灌注期间的功能恢复和心肌损伤（乳酸脱氢酶释放和梗死面积）。在存在或不存在PKA、Epac和PKC抑制剂的情况下，使用细胞可渗透的cAMP类似物诱导灌注心脏中PKA和/或Epac的激活。使用H9C2细胞和心肌细胞评估Epac的激活情况及其对钙瞬变的影响。

主要结果

发现选择性激活PKA或Epac均可触发正性肌力作用，当两条通路同时激活时，该作用显著增强。只有PKA和Epac的联合激活可诱导对I/R损伤的显著心脏保护作用。这伴随着PKCε的激活，并被PKA、Epac或PKC的抑制剂所抑制。

结论与意义

PKA和Epac的同时激活可诱导相加的正性肌力作用，并赋予对I/R损伤的最佳且显著的心脏保护作用。后一种作用由PKCε的激活介导。这项工作引入了一种新的治疗方法和靶点来保护心脏免受心脏损伤。

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