Zhang Yuhong, Ding Yanqing, Li Min, Yuan Jing, Yu Youhui, Bi Xueying, Hong Huiqi, Ye Jiantao, Liu Peiqing
Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou 510006, China.
State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510006, China.
Acta Pharm Sin B. 2022 May;12(5):2374-2390. doi: 10.1016/j.apsb.2021.09.020. Epub 2021 Sep 25.
Pathological cardiac hypertrophy serves as a significant foundation for cardiac dysfunction and heart failure. Recently, growing evidence has revealed that microRNAs (miRNAs) play multiple roles in biological processes and participate in cardiovascular diseases. In the present research, we investigate the impact of miRNA-34c-5p on cardiac hypertrophy and the mechanism involved. The expression of miR-34c-5p was proved to be elevated in heart tissues from isoprenaline (ISO)-infused mice. ISO also promoted miR-34c-5p level in primary cultures of neonatal rat cardiomyocytes (NRCMs). Transfection with miR-34c-5p mimic enhanced cell surface area and expression levels of foetal-type genes atrial natriuretic factor () and -myosin heavy chain () in NRCMs. In contrast, treatment with miR-34c-5p inhibitor attenuated ISO-induced hypertrophic responses. Enforced expression of miR-34c-5p by tail intravenous injection of its agomir led to cardiac dysfunction and hypertrophy in mice, whereas inhibiting miR-34c-5p by specific antagomir could protect the animals against ISO-triggered hypertrophic abnormalities. Mechanistically, miR-34c-5p suppressed autophagic flux in cardiomyocytes, which contributed to the development of hypertrophy. Furthermore, the autophagy-related gene 4B (ATG4B) was identified as a direct target of miR-34c-5p, and miR-34c-5p was certified to interact with 3' untranslated region of mRNA by dual-luciferase reporter assay. miR-34c-5p reduced the expression of ATG4B, thereby resulting in decreased autophagy activity and induction of hypertrophy. Inhibition of miR-34c-5p abolished the detrimental effects of ISO by restoring ATG4B and increasing autophagy. In conclusion, our findings illuminate that miR-34c-5p participates in ISO-induced cardiac hypertrophy, at least partly through suppressing ATG4B and autophagy. It suggests that regulation of miR-34c-5p may offer a new way for handling hypertrophy-related cardiac dysfunction.
病理性心脏肥大是心脏功能障碍和心力衰竭的重要基础。最近，越来越多的证据表明，微小RNA（miRNA）在生物过程中发挥多种作用，并参与心血管疾病。在本研究中，我们探讨了miRNA-34c-5p对心脏肥大的影响及其相关机制。事实证明，在注射异丙肾上腺素（ISO）的小鼠心脏组织中，miR-34c-5p的表达升高。ISO还可促进原代培养的新生大鼠心肌细胞（NRCMs）中miR-34c-5p的水平。用miR-34c-5p模拟物转染可增加NRCMs的细胞表面积以及胎儿型基因心房利钠肽（）和β-肌球蛋白重链（）的表达水平。相反，用miR-34c-5p抑制剂处理可减弱ISO诱导的肥大反应。通过尾静脉注射其激动剂强制表达miR-34c-5p会导致小鼠心脏功能障碍和肥大，而通过特异性拮抗剂抑制miR-34c-5p可以保护动物免受ISO引发的肥大异常。机制上，miR-34c-5p抑制心肌细胞中的自噬通量，这有助于肥大的发展。此外，自噬相关基因4B（ATG4B）被确定为miR-34c-5p的直接靶点，并且通过双荧光素酶报告基因检测证实miR-34c-5p与ATG4B mRNA的3'非翻译区相互作用。miR-34c-5p降低了ATG4B的表达，从而导致自噬活性降低并诱导肥大。抑制miR-34c-5p可通过恢复ATG4B和增加自噬来消除ISO的有害作用。总之，我们的研究结果表明，miR-34c-5p至少部分通过抑制ATG4B和自噬参与ISO诱导的心脏肥大。这表明对miR-34c-5p的调控可能为处理肥大相关的心脏功能障碍提供一种新方法。
