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首页> 外文期刊>Journal of Molecular and Cellular Cardiology >Mitochondrial ROS generation following acetylcholine-induced EGF receptor transactivation requires metalloproteinase cleavage of proHB-EGF.
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Mitochondrial ROS generation following acetylcholine-induced EGF receptor transactivation requires metalloproteinase cleavage of proHB-EGF.

机译：乙酰胆碱诱导的EGF受体反式激活后，线粒体ROS的产生需要proHB-EGF的金属蛋白酶裂解。

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摘要

Acetylcholine (ACh) mimics ischemic preconditioning by a mechanism dependent on phosphatidylinositol 3-kinase (PI3-kinase) and reactive oxygen species (ROS). In other tissues muscarinic receptors activate a metalloproteinase, which liberates surface-associated heparin-binding epidermal growth factor (HB-EGF) and causes transactivation of epidermal growth factor receptors (EGFRs) with activation of PI3-kinase. We tested whether this pathway is operative in myocardium. Adult rabbit cardiomyocytes were incubated in reduced MitoTracker Red, which fluoresces after ROS exposure. ACh caused a 36 +/- 6% increase in fluorescence (P < 0.001) and metalloproteinase inhibitor III (MPI) abolished this increase. Both exogenous EGF as well as HB-EGF caused similar increases in the ROS signal (41 +/- 12%, P = 0.005 and 40 +/- 7%, P < 0.001, respectively). The ROS burst from HB-EGF was unaffected by MPI (37 +/- 6%, P = 0.002), confirming that inhibition of metalloproteinase activity blocked ACh's effect at a site upstream of EGFR. CRM-197, which inhibits HB-EGF activity, also blocked ACh-induced ROS generation, again implicating release of HB-EGF as a necessary step for ROS generation. An HB-EGF-neutralizing antibody also prevented ACh-induced increase in ROS. In isolated, perfused rabbit hearts ACh increased phosphorylation of EGFR by 127.4 +/- 43.7%, and this increase was abolished by MPI. Finally, ACh decreased infarct size from 30.1 +/- 2.9% of the risk zone in control hearts to 13.7 +/- 3.0% (P = 0.002), and this protection could be abolished by co-treatment with MPI (28.7 +/- 2.6%, P = n.s. vs. control). Stimulation of a second G(i)-protein-coupled receptor by the delta-opioid agonist [D-Ala(2), D-Leu(5)]-enkephalin acetate (DADLE) also protected the heart (9.1 +/- 2.0% infarction, P < 0.005 vs. control), and this protection was similarly blocked by MPI (28.9 +/- 2.3% infarction). We conclude that ACh-induced ROS generation in myocytes is mediated via transactivation of EGFR through metalloproteinase-dependent release of HB-EGF, and that this pathway is also operative in the intact heart and is required for ACh's cardioprotection.
机译：乙酰胆碱（ACh）通过依赖于磷脂酰肌醇3-激酶（PI3-激酶）和活性氧（ROS）的机制模拟缺血预处理。在其他组织中，毒蕈碱受体激活金属蛋白酶，该酶释放与表面相关的肝素结合表皮生长因子（HB-EGF），并通过激活PI3-激酶引起表皮生长因子受体（EGFR）的反式激活。我们测试了该途径在心肌中是否有效。将成年兔心肌细胞在减少的MitoTracker Red中孵育，后者在ROS暴露后发出荧光。 ACh导致荧光增加36 +/- 6％（P <0.001），金属蛋白酶抑制剂III（MPI）取消了这种增加。外源性EGF和HB-EGF都引起ROS信号的相似增加（分别为41 +/- 12％，P = 0.005和40 +/- 7％，P <0.001）。 MPI不会影响HB-EGF的ROS爆发（37 +/- 6％，P = 0.002），这证实了金属蛋白酶活性的抑制在EGFR上游位点阻断了ACh的作用。抑制HB-EGF活性的CRM-197也阻断了ACh诱导的ROS生成，再次暗示释放HB-EGF是ROS生成的必要步骤。 HB-EGF中和抗体也可以防止ACh诱导的ROS升高。在离体的灌注兔心脏中，ACh使EGFR的磷酸化增加了127.4 +/- 43.7％，MPI取消了这种增加。最后，ACh将梗死面积从对照心脏的危险区域的30.1 +/- 2.9％减少到13.7 +/- 3.0％（P = 0.002），并且可以通过与MPI共同治疗（28.7 +/-）取消这种保护。 2.6％，P = ns（相对于对照）。阿片类阿片激动剂[D-Ala（2），D-Leu（5）]-乙酸脑啡肽（DADLE）对第二个G（i）蛋白偶联受体的刺激也保护了心脏（9.1 +/- 2.0 ％梗塞，相对于对照，P ＜0.005），并且该保护类似地被MPI（28.9 +/- 2.3％梗塞）阻断。我们得出的结论是，通过金属蛋白酶依赖性释放的HB-EGF，EGFR的反式激活介导了ACh诱导的心肌细胞中ROS的产生，并且该途径在完整的心脏中也有效，并且是ACh的心脏保护所必需的。

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