Hypoxia induces connexin 43 dysregulation by modulating matrix metalloproteinases via MAPK signaling.
Hypoxia induces connexin 43 dysregulation by modulating matrix metalloproteinases via MAPK signaling.
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缺氧通过 MAPK 信号传导调节基质金属蛋白酶，诱导连接蛋白 43 失调
DOI：
10.1007/s11010-013-1793-5
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发表时间：
2013-12
影响因子：
4.3
通讯作者：
Alain LA
中科院分区：
文献类型：
--
作者：
Wu X;Huang W;Luo G;Alain LA
连接蛋白43（Cx43）是心室肌差距连接中的主要结构蛋白，是决定其电特性的主要因素。观察基质金属蛋白酶（MMPs）、丝裂原活化蛋白激酶（MAPK）信号通路、转录因子NF-κ B和激活蛋白-1（AP-1）/c-Jun对H9 c2心肌细胞Cx43基因表达的调节作用。MAPK信号通路（MEK/ERK 1/2和PI 3 K）和转录因子NF-kB和AP-1/c-Jun被抑制，然后使用Western印迹分析评估Cx43表达，并使用明胶酶谱法评估MMP-9活性。缺氧使Cx43蛋白水平降低约30- 50%。MMP抑制剂强力霉素（10 μg/mL）在6 h时可明显减弱缺氧诱导的Cx43蛋白表达下调。缺氧诱导的Cx43蛋白表达下降在6和12 h时可被MEK/ERK 12抑制剂U 0126（10 μM）显著逆转; PI 3 K抑制剂LY 294002（30 μM）下调Cx43表达。缺氧诱导的MMP-9活化被LY 294002，U 0126，尤其是U 0126处理抑制。NF-kB抑制剂JSH-23（30 μM）和AP-1/c-Jun抑制剂SP 600125（10 μM）可减弱Cx43的丢失。这些结果表明，MAPK信号传导以及NF-kB和MMPs活性在Cx43表达的调节中发挥重要作用。
Connexin 43 (Cx43) is a major structural protein found in the gap junctions of the ventricular myocardium and a major determinant of its electrical properties. The effects of matrix metalloproteinases (MMPs), the mitogen-activated protein kinase (MAPK) signaling pathway, transcription factor NF-kB, and activator protein-1 (AP-1)/c-Jun on the regulation of Cx43 gene expression in H9c2 cardiomyocytes were assessed. The MAPK signaling pathway (MEK/ERK1/2 and PI3K) and transcription factors NF-kB and AP-1/c-Jun were inhibited, then Cx43 expression was assessed using Western blot analysis, and MMP-9 activity was assessed using gelatin zymography. Hypoxia decreased the Cx43 protein level by approximately 30–50 %. Doxycycline (10 μg/mL), an inhibitor of MMP, markedly attenuated the hypoxia-induced downregulation of Cx43 protein expression at 6 h. The hypoxia-induced decrease in Cx43 protein expression was significantly reversed by U0126 (10 μM), a MEK/ERK1/2 inhibitor, at 6 and 12 h; LY294002 (30 μM), a PI3K inhibitor, downregulated Cx43 expression. Hypoxia-induced MMP-9 activation was inhibited by treatment with LY294002, U0126, and, most especially, U0126. JSH-23 (30 μM), an NF-kB inhibitor, and SP600125 (10 μM), an AP-1/c-Jun inhibitor, attenuated the loss of Cx43. These results suggest that MAPK signaling and the activities NF-kB and MMPs play an important roles in the regulation of Cx43 expression.