Liu Zhi-Yong, Lu Mingjun, Liu Jing, Wang Zhao-Ning, Wang Wei-Wei, Li Yong, Song Zhi-Jing, Xu Lingling, Liu Qian, Li Feng-Hua
Department of Cardiology, Dezhou People's Hospital, Dezhou, Shandong 253014, P.R. China.
Department of Cardiology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, P.R. China.
Exp Ther Med. 2020 Sep;20(3):2113-2121. doi: 10.3892/etm.2020.8901. Epub 2020 Jun 17.
Cardiac fibrosis is involved in adverse cardiac remodeling and heart failure, which is the leading cause of deteriorated cardiac function. Accumulative evidence has elucidated that microRNAs (miRNAs) play important roles in the pathogenesis of cardiac fibrosis. However, the exact molecular mechanism underlying miR-144 in cardiac fibrosis remains unknown. In the present study, a transverse aortic constriction (TAC) mouse model and angiotensin II (Ang II)-induced cardiac fibroblasts (CFs) were constructed in order to investigate the expression levels of miR-144. It was demonstrated that miR-144 was significantly downregulated following pathological stimuli. CFs infected with miR-144 mimics were then used to test the effect of miR-144 on CF activation . The results revealed that overexpression of miR-144 led to a dramatically decreased proliferation and migration ability in CFs, as well as the transformation from fibroblasts to myofibroblasts, which was characterized by the decreased expression of collagen-I, collagen-III, CTGF, fibronectin and α-SMA. By contrast, such effects could be reversed by miR-144 knockdown. Mechanistically, the bioinformatics analysis and luciferase reporter assay in the present study demonstrated that cAMP response element-binding protein (CREB) was a direct target of miR-144, and the expression of CREB was attenuated by miR-144. The results of the present study demonstrated that miR-144 played a key role in CF activation, partially by targeting CREB, which further suggested that the overexpression of miR-144 may be a promising strategy for the treatment of cardiac fibrosis.
心脏纤维化参与不良心脏重塑和心力衰竭，而心力衰竭是心脏功能恶化的主要原因。越来越多的证据表明，微小RNA（miRNA）在心脏纤维化的发病机制中起重要作用。然而，miR-144在心脏纤维化中的确切分子机制仍不清楚。在本研究中，构建了横向主动脉缩窄（TAC）小鼠模型和血管紧张素II（Ang II）诱导的心脏成纤维细胞（CFs），以研究miR-144的表达水平。结果表明，在病理刺激后miR-144显著下调。然后用感染了miR-144模拟物的CFs来测试miR-144对CF激活的影响。结果显示，miR-144的过表达导致CFs的增殖和迁移能力显著降低，以及从成纤维细胞向肌成纤维细胞的转变，其特征是I型胶原、III型胶原、结缔组织生长因子、纤连蛋白和α-平滑肌肌动蛋白的表达降低。相比之下，这种作用可通过敲低miR-144来逆转。机制上，本研究中的生物信息学分析和荧光素酶报告基因检测表明，环磷酸腺苷反应元件结合蛋白（CREB）是miR-144的直接靶点，且miR-144可使CREB的表达减弱。本研究结果表明，miR-144在CF激活中起关键作用，部分是通过靶向CREB，这进一步表明miR-144的过表达可能是治疗心脏纤维化的一种有前景的策略。
