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Inhibition of histone demethylase JMJD1C attenuates cardiac hypertrophy and fibrosis induced by angiotensin II
Journal of Receptors and Signal Transduction ( IF 2.8 ) Pub Date : 2020-03-03 , DOI: 10.1080/10799893.2020.1734819
Shenqian Zhang 1, 2 , Ying Lu 2 , Chenyang Jiang 1
Affiliation  

Abstract Pathological cardiac hypertrophy is a major risk factor for cardiovascular morbidity and mortality. Histone demethylases (KDMs) are emerging regulators of transcriptional reprograming in cancer, however, their potential role in abnormal heart growth and fibrosis remains largely unknown. The aim of this current study was to examine the role of JMJD1C, an H3K9me2 specific demethylase, in angiotensin II (Ang II) induced cardiac hypertrophy and fibrosis. In this study, we observed that Ang II could increase the expression of JMJD1C detected by Western blot and RT-qPCR in vitro and in vivo. Immunofluorescence staining showed that the treatment of Ang II could increase cardiomyocyte size. RT-qPCR results have shown that Ang II could increase the expression of cell hypertrophic and fibrotic markers in H9c2 cells. Whereas, inhibition of JMJD1C by shRNA and JIB-04, a small molecule histone demethylase inhibitor, significantly reduced Ang II-induced cell hypertrophy, and hypertrophic and fibrotic marker overexpression. Furthermore, cardiomyocyte JMJD1C knockdown decreased Tissue Inhibitor of Metalloproteinases 1 (TIMP1) transcription with pro-fibrotic activity. In conclusion, JMJD1C plays an important role in Ang II-induced cardiac hypertrophy and fibrosis by activating TIMP1 transcription, targeting of JMJD1C may be an effective strategy for the treatment of Ang II-associated cardiac diseases.

中文翻译:

抑制组蛋白去甲基化酶 JMJD1C 减轻血管紧张素 II 诱导的心脏肥大和纤维化

摘要 病理性心脏肥大是心血管发病率和死亡率的主要危险因素。组蛋白去甲基化酶 (KDMs) 是癌症转录重编程的新兴调节因子,然而,它们在心脏异常生长和纤维化中的潜在作用仍然未知。本研究的目的是检查 JMJD1C(一种 H3K9me2 特异性去甲基化酶)在血管紧张素 II (Ang II) 诱导的心脏肥大和纤维化中的作用。在这项研究中,我们观察到 Ang II 可以增加体外和体内蛋白质印迹和 RT-qPCR 检测到的 JMJD1C 的表达。免疫荧光染色显示,Ang II 的处理可以增加心肌细胞的大小。RT-qPCR结果表明Ang II可以增加H9c2细胞中细胞肥大和纤维化标志物的表达。然而,shRNA 和 JIB-04(一种小分子组蛋白去甲基化酶抑制剂)对 JMJD1C 的抑制显着降低了 Ang II 诱导的细胞肥大以及肥大和纤维化标志物的过度表达。此外,心肌细胞 JMJD1C 敲低降低了具有促纤维化活性的金属蛋白酶组织抑制剂 1 (TIMP1) 转录。总之,JMJD1C 通过激活 TIMP1 转录在 Ang II 诱导的心脏肥大和纤维化中起重要作用,靶向 JMJD1C 可能是治疗 Ang II 相关心脏病的有效策略。心肌细胞 JMJD1C 敲低降低了具有促纤维化活性的金属蛋白酶组织抑制剂 1 (TIMP1) 转录。总之,JMJD1C 通过激活 TIMP1 转录在 Ang II 诱导的心脏肥大和纤维化中起重要作用,靶向 JMJD1C 可能是治疗 Ang II 相关心脏病的有效策略。心肌细胞 JMJD1C 敲低降低了具有促纤维化活性的金属蛋白酶组织抑制剂 1 (TIMP1) 转录。总之,JMJD1C 通过激活 TIMP1 转录在 Ang II 诱导的心脏肥大和纤维化中起重要作用,靶向 JMJD1C 可能是治疗 Ang II 相关心脏病的有效策略。
更新日期:2020-03-03
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