Microarray analysis and functional characterization revealed NEDD4-mediated cardiomyocyte autophagy induced by angiotensin II
Microarray analysis and functional characterization revealed NEDD4-mediated cardiomyocyte autophagy induced by angiotensin II
复制标题
微阵列分析和功能表征揭示血管紧张素 II 诱导的 NEDD4 介导的心肌细胞自噬
DOI：
10.1007/s12192-018-00957-x
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发表时间：
2019-01-01
影响因子：
3.8
通讯作者：
Wang, Guokun
中科院分区：
文献类型：
--
作者：
Gu, Ying;Yang, Fan;Wang, Guokun
自噬是一种高度调控的细胞内过程，通过降解受损的蛋白质和细胞器来维持细胞稳态。心肌细胞自噬活性的失调与各种心脏病有关。然而，心肌细胞自噬的潜在机制尚不清楚。在本研究中，血管紧张素II （0.1 μmol/L）诱导心肌细胞自噬增强，表现为双膜自噬体增加，BECN1表达增加，LC3-I向LC3-II转化。微阵列分析显示，在血管紧张素ii处理的心肌细胞中，共有197个基因差异表达，其中22个基因上调，175个基因下调。基因本体功能富集分析表明，近50%的差异表达基因与生物过程中的代谢和能量维持有关。途径分析表明，最常见的途径涉及代谢、柠檬酸循环和呼吸电子传递。基于KEGG数据库，发现10个差异表达基因参与自噬信号通路。通过PPI网络分析，预测了高度中枢基因对心肌细胞自噬活性的调控作用。在血管紧张素II治疗过程中，NEDD4在心肌细胞中表现出明显的时间依赖性表达增加模式。此外，抑制NEDD4可显著降低血管紧张素II诱导的心肌细胞自噬。综上所述，通过微阵列技术结合生物信息学分析筛选心肌细胞自噬相关基因。NEDD4在心肌细胞自噬中的作用可能为寻找心脏病的治疗靶点提供有价值的线索。
Autophagy is a highly regulated intracellular process to maintain cellular homeostasis by degrading damaged proteins and organelles. Dysregulation of autophagic activity in cardiomyocytes is implicated in various heart diseases. However, the underlying mechanisms of cardiomyocyte autophagy are not yet known. In this study, the enhanced cardiomyocyte autophagy was induced by angiotensin II (0.1 μmol/L), demonstrated by the increase of double-membraned autophagosomes, BECN1 expression, and the conversion of LC3-I to LC3-II. Microarray assay showed that a total of 197 genes were differentially expressed in angiotensin II–treated cardiomyocytes, including 22 upregulated and 175 downregulated. Gene ontology functional enrichment analysis showed that nearly 50% of differentially expressed genes were related to metabolism and energy maintenance in biological process. Pathway analysis showed that most frequently represented pathways were involved in metabolism and the citric acid cycle and respiratory electron transport. Based on KEGG database, 10 differentially expressed genes were found to be involved in autophagic signaling pathways. The hub genes with high degree were predicted to regulate cardiomyocyte autophagy activity by PPI network analysis. NEDD4, the top focus hub gene, showed a clear time-dependent increased expression pattern in cardiomyocytes during angiotensin II treatment. Moreover, inhibition of NEDD4 could significantly reduce cardiomyocyte autophagy induced by angiotensin II. In summary, the cardiomyocyte autophagy–related genes were screened by microarray assay combining with bioinformatics analysis. The role of NEDD4 on cardiomyocyte autophagy might provide valuable clues to finding therapeutic targets for heart diseases.