Zhou Xue-Liang, Xu Hua, Liu Zhi-Bo, Wu Qi-Cai, Zhu Rong-Rong, Liu Ji-Chun
Department of Cardiac Surgery, The First Affiliated Hospital, Nanchang University, Nanchang, China.
Department of Obstetrics and Gynecology, Jiangxi Province hospital of integrated traditional, Nanchang, 330006, China.
J Cell Mol Med. 2018 Aug;22(8):3816-3824. doi: 10.1111/jcmm.13654. Epub 2018 May 28.
Myocardial fibrosis after myocardial infarction (MI) is a leading cause of heart diseases. MI activates cardiac fibroblasts (CFs) and promotes CF to myofibroblast transformation (CMT). This study aimed to investigate the role of miR-21 in the regulation of CMT and myocardial fibrosis. Primary rat CFs were isolated from young SD rats and treated with TGF-β1, miR-21 sponge or Jagged1 siRNA. Cell proliferation, invasion and adhesion were detected. MI model was established in male SD rats using LAD ligation method and infected with recombinant adenovirus. The heart function and morphology was evaluated by ultrasonic and histological analysis. We found that TGF-β1 induced the up-regulation of miR-21 and down-regulation of Jagged1 in rat CFs. Luciferase assay showed that miR-21 targeted 3'-UTR of Jagged1 in rat CFs. miR-21 sponge inhibited the transformation of rat CFs into myofibroblasts, and abolished the inhibition of Jagged1 mRNA and protein expression by TGF-β1. Furthermore, these effects of miR-21 sponge on rat CFS were reversed by siRNA mediated knockdown of Jagged1. In vivo, heart dysfunction and myocardial fibrosis in MI model rats were partly improved by miR-21 sponge but were aggravated by Jagged1 knockdown. Taken together, these results suggest that miR-21 promotes cardiac fibroblast-to-myofibroblast transformation and myocardial fibrosis by targeting Jagged1. miR-21 and Jagged1 are potential therapeutic targets for myocardial fibrosis.
心肌梗死后的心肌纤维化是心脏病的主要原因。心肌梗死激活心脏成纤维细胞（CFs）并促进CF向肌成纤维细胞转化（CMT）。本研究旨在探讨miR-21在调节CMT和心肌纤维化中的作用。从幼年SD大鼠中分离出原代大鼠CFs，并用TGF-β1、miR-21海绵或Jagged1 siRNA处理。检测细胞增殖、侵袭和黏附情况。采用左冠状动脉前降支结扎法建立雄性SD大鼠心肌梗死模型，并感染重组腺病毒。通过超声和组织学分析评估心脏功能和形态。我们发现TGF-β1诱导大鼠CFs中miR-21上调和Jagged1下调。荧光素酶报告基因检测显示miR-21靶向大鼠CFs中Jagged1的3'-UTR。miR-21海绵抑制大鼠CFs向肌成纤维细胞的转化，并消除TGF-β1对Jagged1 mRNA和蛋白表达的抑制作用。此外，miR-21海绵对大鼠CFs的这些作用被siRNA介导的Jagged1敲低所逆转。在体内，miR-21海绵部分改善了心肌梗死模型大鼠的心脏功能障碍和心肌纤维化，但Jagged1敲低使其加重。综上所述，这些结果表明miR-21通过靶向Jagged1促进心脏成纤维细胞向肌成纤维细胞转化和心肌纤维化。miR-21和Jagged1是心肌纤维化的潜在治疗靶点。
