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Front. Physiol. | doi: 10.3389/fphys.2019.01445

Down-Regulation of miR-34a-5p Potentiates Protective Effect of Adipose-Derived Mesenchymal Stem Cells against Ischemic Myocardial Infarction by Stimulating the Expression of CTRP9

Chi-Feng Weng1, Ching-Feng Wu2, Shao-Hsuan Kao3, Jeen-Chen Chen2 and  Hui-Han Lin2*
  • 1Hsinchu Mackay Memorial Hospital, Taiwan
  • 2China Medical University Hospital, Taiwan
  • 3Chung Shan Medical University, Taiwan

Adipose-derived stem cells (ADSCs) have shown great promise for the treatment of myocardial infarction (MI), although their potential therapeutic mechanism remains poorly understood. Growing evidence has implicated microRNAs (miRNAs or miRs) in the biological processes whereby ADSCs could ameliorate cardiovascular disease. In this study, we explored the contribution of miR-34a-5p down-regulation to the protective actions of ADSCs against MI. We initially identified the interaction between miR-34a-5p and C1q/tumor necrosis factor-related protein-9 (CTRP9) through in silico analysis. We next tested the effects of miR-34a-5p and CTRP9 on the expression of extracellular signal-regulated kinase 1 (ERK1), matrix metalloproteinase-9 (MMP-9), nuclear factor (erythroid-derived 2)-like 2 (NRF2) and antioxidant proteins (manganese superoxide dismutase [MnSOD], heme oxygenase-1 [HO-1]) through gain- and loss-of-function tests. In other experiments, we assessed the proliferation, migration, and apoptosis of ADSCs using the EdU assay, scratch test, Transwell assay and flow cytometry. Finally, we studied whether miR-34a-5p/CTRP9 axis could modulate the protective effect of ADSCs against MI during stem cell transplantation in MI mouse models. miR-34a-5p could target and down-regulate CTRP9 in cardiomyocytes. Down-regulated miR-34a-5p increased the expression of ERK1, MMP-9, NRF2, MnSOD and HO-1, whereas down-regulation of miR-34a-5p or up-regulation CTRP9 in vitro promoted ADSC proliferation and migration and inhibited ADSC apoptosis. Moreover, miR-34a-5p down-regulation or CTRP9 up-regulation promoted the protective role of ADSCs against MI damage in vivo. Thus, inhibition of miR-34a-5p may facilitate ADSC’s protective function against MI damage by stimulating the expression of CTRP9.

Keywords: Myocardial Infarction, MicroRNA-34a-5p, C1q/tumor necrosis factor-related protein-9, adipose-derived stem cells, proliferation, Migration

Received: 05 May 2019; Accepted: 08 Nov 2019.

Copyright: © 2019 Weng, Wu, Kao, Chen and Lin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mx. Hui-Han Lin, China Medical University Hospital, Taichung, 404, Taiwan,