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MicroRNA-210 repression facilitates advanced glycation end-product (AGE)-induced cardiac mitochondrial dysfunction and apoptosis via JNK activation
Journal of Cellular Biochemistry ( IF 4 ) Pub Date : 2021-09-21 , DOI: 10.1002/jcb.30146
Kuan-Ho Lin, Shang-Chuan Ng, Catherine R. Paul, Hong-Chen Chen, Ren-You Zeng, Jian-Sheng Liu, Viswanadha V. Padma, Chih-Yang Huang, Wei-Wen Kuo

Hyperglycemia results in the formation of reactive oxygen species which in turn causes advanced glycation end products (AGEs) formation, leading to diabetic cardiomyopathy. Our previous study showed that AGE-induced reactive oxygen species-dependent apoptosis is mediated via protein kinase C delta (PKCδ)-enhanced mitochondrial damage in cardiomyocytes. By using microRNA (miRNA) database, miRNA-210 was predicted to target c-Jun N-terminal kinase (JNK), which were previously identified as downstream of PKCδ in regulating mitochondrial function. Therefore, we hypothesized that miR-210 mediates PKCδ-dependent upregulation of JNK to cause cardiac mitochondrial damage and apoptosis following AGE exposure. AGE-exposed cells showed activated cardiac JNK, PKCδ, and apoptosis, which were reversed by treatment with a JNK inhibitor and PKCδ-KD (deficient kinase). Cardiac miR-210 and mitochondrial function were downregulated following AGE exposure. Furthermore, JNK was upregulated and involved in AGE-induced mitochondrial damage. Interestingly, luciferase activity of the miR-210 mimic plus JNK WT-3′-untranslated region overexpressed group was significantly lower than that of miR-210 mimic plus JNK MT-3′UTR group, indicating that JNK is a target of miR-210. Moreover, JNK activation induced by AGEs was reduced by treatment with the miR-210 mimic and reversed by treatment with the miR-210 inhibitor, indicating the regulatory function of miR-210 in JNK activation following AGE exposure. Additionally, JNK-dependent mitochondrial dysfunction and apoptosis were reversed following treatment with the miR-210 mimic, while the miR-210 inhibitor showed no effect on JNK-induced mitochondrial dysfunction and apoptosis in AGE-exposed cardiac cells. Taken together, our study showed that PKCδ-enhanced JNK-dependent mitochondrial damage is mediated through the reduction of miR-210 in cardiomyocytes following AGE exposure.

中文翻译:

MicroRNA-210 抑制通过 JNK 激活促进晚期糖基化终产物 (AGE) 诱导的心脏线粒体功能障碍和细胞凋亡

高血糖会导致活性氧的形成,进而导致晚期糖基化终产物 (AGEs) 的形成,从而导致糖尿病性心肌病。我们之前的研究表明,AGE 诱导的活性氧依赖性细胞凋亡是通过蛋白激酶 C δ (PKCδ) 增强的心肌细胞线粒体损伤介导的。通过使用 microRNA (miRNA) 数据库,预测 miRNA-210 靶向 c-Jun N-末端激酶 (JNK),该激酶先前被确定为 PKCδ 下游调节线粒体功能。因此,我们假设 miR-210 介导 PKCδ 依赖性 JNK 上调,从而在 AGE 暴露后引起心脏线粒体损伤和细胞凋亡。AGE 暴露的细胞显示活化的心脏 JNK、PKCδ 和凋亡,通过用 JNK 抑制剂和 PKCδ-KD(缺乏激酶)处理可逆转。AGE 暴露后心脏 miR-210 和线粒体功能下调。此外,JNK 上调并参与 AGE 诱导的线粒体损伤。有趣的是,miR-210模拟物加JNK WT-3'-非翻译区过表达组的荧光素酶活性显着低于miR-210模拟物加JNK MT-3'UTR组,表明JNK是miR-210的靶标. 此外,由 AGEs 诱导的 JNK 激活通过 miR-210 模拟物处理减少,并通过 miR-210 抑制剂处理逆转,表明 miR-210 在 AGE 暴露后在 JNK 激活中的调节功能。此外,在用 miR-210 模拟物治疗后,JNK 依赖性线粒体功能障碍和细胞凋亡被逆转,而 miR-210 抑制剂对 JNK 诱导的 AGE 暴露的心肌细胞中的线粒体功能障碍和细胞凋亡没有影响。总之,我们的研究表明,PKCδ 增强的 JNK 依赖性线粒体损伤是通过 AGE 暴露后心肌细胞中 miR-210 的减少介导的。
更新日期:2021-09-21
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