miRNA-130b is required for the ERK/FOXM1 pathway activation-mediated protective effects of isosorbide dinitrate against mesenchymal stem cell senescence induced by high glucose

Xu,Jianfeng; Huang,Zheyong; Lin,Li; Fu,Mingqiang; Song,Yanan; Shen,Yunli; Ren,Daoyuan; Gao,Yanhua; Su,Yangang; Zou,Yunzeng; Chen,Yueguang; Zhang,Dadong; Hu,Wei; Qian,Juying; Ge,Junbo

doi:10.3892/ijmm.2014.1985

miRNA-130b is required for the ERK/FOXM1 pathway activation-mediated protective effects of isosorbide dinitrate against mesenchymal stem cell senescence induced by high glucose

Authors:
- Jianfeng Xu
- Zheyong Huang
- Li Lin
- Mingqiang Fu
- Yanan Song
- Yunli Shen
- Daoyuan Ren
- Yanhua Gao
- Yangang Su
- Yunzeng Zou
- Yueguang Chen
- Dadong Zhang
- Wei Hu
- Juying Qian
- Junbo Ge
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Affiliations: Department of Cardiology, Minhang Hospital, Ruijin Hospital Group, Shanghai Jiaotong University School of Medicine, Shanghai 201199, P.R. China, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China, Department of Cardiology, Eastern Hospital, Tongji University, Shanghai 200120, P.R. China
Published online on: October 29, 2014 https://doi.org/10.3892/ijmm.2014.1985
Pages: 59-71
Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

The present study was carried out to investigate the hypothesis that organic nitrates can attenuate the senescence of mesenchymal stem cells (MSCs), a superior cell source involved in the regeneration and repair of damaged tissue. MSCs were treated with high glucose (HG) in order to induce senescence, which was markedly attenuated by pre-treatment with isosorbide dinitrate (ISDN), a commonly used nitrate, as indicated by senescence-associated galactosidase (SA-β-gal) activity, p21 expression, as well as by the mRNA levels of DNA methyltransferase 1 (DNMT1) and differentiated embryo chondrocyte expressed gene 1 (DEC1), which are senescence-related biomarkers. It was also found that the senescent MSCs (induced by HG glucose) exhibited a marked downregulation in ERK activity and forkhead box M1 (FOXM1) expression, which was reversed by ISDN preconditioning. Of note, the inhibition of ERK phosphorylation or the downregulation of FOXM1 statistically abolished the favourable effects of ISDN. In addition, the investigation of the senescence-associated miR-130 family suggested that miR-130b mediates the beneficial effects of ISDN; it was found that the protective effects of ISDN against the senescence of MSCs were prominently reversed by the knockdown of miR-130b. Furthermore, the downregulation of ERK phosphorylation or FOXM1 expression decreased the miR-130b expression level; however, the suppression of miR-130b demonstrated no significant impact on ERK phosphorylation or FOXM1 expression. Taken together, to the best of our knowledge, the present study is the first to demonstrate the favourable effects of ISDN against HG-induced MSC senescence, which are mediated through the activation of the ERK/FOXM1 pathway and the upregulation of miR-130b.

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