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首页> 外文期刊>Journal of Inorganic Biochemistry: An Interdisciplinary Journal >Zinc pyrithione inhibits caspase-3 activity, promotes ErbB1-ErbB2 heterodimerization and suppresses ErbB2 downregulation in cardiomyocytes subjected to ischemia/reperfusion
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Zinc pyrithione inhibits caspase-3 activity, promotes ErbB1-ErbB2 heterodimerization and suppresses ErbB2 downregulation in cardiomyocytes subjected to ischemia/reperfusion

机译:巯氧吡啶锌抑制caspase-3活性,促进ErbB1-ErbB2异二聚化并抑制缺血/再灌注心肌细胞中ErbB2下调。

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摘要

Heart tissue becomes zinc-depleted and the capacity to mobilize labile zinc is diminished, indicating zinc dyshomeostasis during ischemia/reperfusion (I/R). Apparently, zinc pyrithione restores the basal zinc levels during I/R and prevents apoptosis by activating phosphatidyl inositol-3-kinase/Akt and targeting mitochondrial permeability transition. Receptor tyrosine kinases of the ErbB family (ErbB1 to ErbB4) are cell surface proteins that can regulate cell growth, proliferation and survival. Previous studies have shown that zinc pyrithione-induced activation of PI3kinase/Akt requires ErbB2 expression. On the other hand, while I/R decreases ErbB2 levels causing cardiomyocyte dysfunction and cell death, zinc pyrithione restores ErbB2 levels and maintains cardiomyocyte function. H9c2 cells expressed all the four ErbBs, although the expression of ErbB1 and ErbB2 were higher compared to ErbB3 and ErbB4. Hypoxia/Reoxygenation (H/R) had opposing effects on the mRNA expression of ErbB1 and ErbB2. ErbB2 mRNA levels were enhanced, but corresponding ErbB2 protein levels decreased after reoxygenation. H/R induced the degradation of ErbB2 in caspase-3 dependent manner, with the formation of a 25 kDa fragment. This fragment could be detected after H/R only upon treatment of the cells with a proteasomal inhibitor, ALLN, suggesting that caspase-mediated cleavage of 185 kDa ErbB2 results in C-terminal cleavage and formation of 25 kDa fragment, which is further degraded by proteasome. Heterodimerization and phosphorylation of ErbB2/ErbB1 which decreased upon reoxygenation, was promoted by zinc pyrithione. Zinc pyrithione effectively suppressed the caspase activation, decreased the proteolytic cleavage of ErbB2, enhanced the phosphorylation and activation of ErbB1-ErbB2 complexes and improved the cell survival after hypoxia/reoxygenation. (C) 2015 Elsevier Inc. All rights reserved.
机译:心脏组织变得缺锌,动员不稳定的锌的能力降低,表明缺血/再灌注(I / R)期间锌动态失衡。显然,巯氧吡啶锌可在I / R期间恢复基础锌水平,并通过激活磷脂酰肌醇3-激酶/ Akt和靶向线粒体通透性转变来防止细胞凋亡。 ErbB家族(ErbB1至ErbB4)的受体酪氨酸激酶是可以调节细胞生长,增殖和存活的细胞表面蛋白。先前的研究表明,巯氧吡啶锌诱导的PI3激酶/ Akt激活需要ErbB2表达。另一方面,虽然I / R降低了引起心肌细胞功能障碍和细胞死亡的ErbB2水平,但是巯氧吡啶锌恢复了ErbB2水平并维持了心肌细胞功能。 H9c2细胞表达了所有四个ErbB,尽管与ErbB3和ErbB4相比,ErbB1和ErbB2的表达更高。缺氧/复氧(H / R)对ErbB1和ErbB2的mRNA表达有相反的影响。复氧后,ErbB2 mRNA水平增强,但相应的ErbB2蛋白水平下降。 H / R以caspase-3依赖性方式诱导ErbB2降解,并形成25 kDa片段。只有在用蛋白酶体抑制剂ALLN处理细胞后,才能在H / R之后检测到该片段,这表明半胱天冬酶介导的185 kDa ErbB2裂解导致C末端裂解和25 kDa片段的形成,并进一步降解。蛋白酶体。巯氧吡啶锌可促进ErbB2 / ErbB1的异二聚化和磷酸化,再氧化后会降低。巯氧吡啶锌可有效抑制caspase活化,减少ErbB2的蛋白水解切割,增强ErbB1-ErbB2复合物的磷酸化和活化,并改善缺氧/复氧后的细胞存活率。 (C)2015 Elsevier Inc.保留所有权利。

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