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首页> 外文期刊>American Journal of Physiology >Essential role of EGFR in cardioprotection and signaling responses to A1 adenosine receptors and ischemic preconditioning.
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Essential role of EGFR in cardioprotection and signaling responses to A1 adenosine receptors and ischemic preconditioning.

机译：EGFR在心脏保护和对A1腺苷受体和缺血预处理的信号传导中的重要作用。

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Transactivation of epidermal growth factor receptor (EGFR) may contribute to specific protective responses (e.g. mediated by delta-opioid, bradykinin, or muscarinic receptors). No studies have assessed EGFR involvement in cardioprotection mediated by adenosine receptors (ARs), and the role of EGFR in ischemic preconditioning (IPC) is unclear. We tested EGFR, matrix metalloproteinase (MMP), and heparin-binding EGF (HB-EGF) dependencies of functional protection via A(1)AR agonism or IPC. Pretreatment of mouse hearts with 100 nM of A(1)AR agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA) or IPC (3 x 1.5-min ischemia/2-min reperfusion) substantially improved recovery from 25-min ischemia, reducing left ventricular diastolic dysfunction up to 50% and nearly doubling pressure development and positive change in pressure over time (+dP/dt). Benefit with both CCPA and IPC was eliminated by inhibitors of EGFR tyrosine kinase (0.3 muM AG1478), MMP (0.3 muM GM6001), or HB-EGF ligand (0.3 ng/ml CRM197), none of which independently altered postischemic outcome. Phosphorylation of myocardial EGFR, Erk1/2, and Akt increased two- to threefold during A(1)AR agonism, with responses blocked by AG1478, GM6001, and CRM197. Studies in HL-1 myocytes confirm A(1)AR-dependent Erk1/2 phosphorylation is negated by AG1478 or GM6001, and reduced with CRM197 (as was Akt activation). These data collectively reveal that A(1)AR- and IPC-mediated functional protection is entirely EGFR and MMP dependent, potentially involving the HB-EGF ligand. Myocardial survival kinase activation (Erk1/2, Akt) by A(1)AR agonism is similarly MMP/HB-EGF/EGFR dependent. Thus MMP-mediated EGFR activation appears essential to cardiac protection and signaling via A(1)ARs and preconditioning.
机译：表皮生长因子受体（EGFR）的反式激活可能有助于特定的保护性反应（例如，由δ阿片类药物，缓激肽或毒蕈碱受体介导）。尚无研究评估EGFR参与由腺苷受体（ARs）介导的心脏保护，并且尚不清楚EGFR在缺血预处理（IPC）中的作用。我们通过A（1）AR激动剂或IPC对功能保护的EGFR，基质金属蛋白酶（MMP）和肝素结合EGF（HB-EGF）依赖性进行了测试。用100 nM的A（1）AR激动剂2-氯-N（6）-环戊基腺苷（CCPA）或IPC（3 x 1.5分钟局部缺血/ 2分钟再灌注）预处理小鼠心脏可显着提高从25分钟局部缺血的恢复，最多可将左心室舒张功能障碍降低50％，并且随着时间的推移压力发展和正压力变化（+ dP / dt）几乎翻倍。 EGFR酪氨酸激酶（0.3μMAG1478），MMP（0.3μMGM6001）或HB-EGF配体（0.3 ng / ml CRM197）的抑制剂消除了CCPA和IPC的益处，这些都没有独立改变缺血后的预后。心肌EGFR，Erk1 / 2和Akt的磷酸化在A（1）AR激动过程中增加了2到3倍，而AG1478，GM6001和CRM197阻止了反应。对HL-1心肌细胞的研究证实，AG1478或GM6001消除了A（1）AR依赖的Erk1 / 2磷酸化，并被CRM197还原（与Akt激活一样）。这些数据共同表明，A（1）AR和IPC介导的功能保护完全依赖EGFR和MMP，可能涉及HB-EGF配体。 A（1）AR激动对心肌生存激酶的激活（Erk1 / 2，Akt）类似地依赖于MMP / HB-EGF / EGFR。因此，MMP介导的EGFR激活似乎对心脏保护和通过A（1）ARs和预处理的信号传导至关重要。

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