Inhibition of MEF2A prevents hyperglycemia-induced extracellular matrix accumulation by blocking Akt and TGF-β1/Smad activation in cardiac fibroblasts

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• 作者：Xueying Chen^a ; Guoliang Liu^b ; Wei Zhang^a ; Jianing Zhang^c ; Yugang Yan^d ; Wenqian Dong^a ; Ershun Liang^a ; Yun Zhang^a ; Mingxiang Zhang^a ; ^{zhangmingxiang@sdu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：MEF2A ; myocyte enhancer factor 2A ; CFs ; cardiac fibroblasts ; NG ; normal glucose ; HG ; high glucose ; OC ; osmotic control ; MAPK ; mitogen-activated protein kinases ; shRNAs ; short-hairpin RNAs ; RNAi ; RNA interference ; STZ ; streptozotocin ; MOI ; multiplicity of infection ; MMP ; matrix metalloproteinase ; TIMP1 ; tissue inhibitor of metalloproteinase ; TGF-β1 ; transforming growth factor-β1 ; JNK ; Jun NH2-terminal kinase ; ERK1/2 ; extracellular-regulated protein kinase 1/2 ; CCK-8 ; Cell Counting Kit-8 ; PE ; phyc
• 刊名：International Journal of Biochemistry and Cell Biology
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：69
• 期：Complete
• 页码：52-61
• 全文大小：2650 K

文摘

Myocyte enhancer factor 2A (MEF2A) functions in muscle-specific and/or growth factor-related transcription and is involved in cell growth, survival, and apoptosis. To evaluate the role of this transcription factor in cardiac fibroblasts (CFs) in diabetes mellitus, we performed a series of in vitro and in vivo experiments. We used short hairpin RNA (shRNA) to inhibit the expression of MEF2A in CFs in vitro. Inhibition of MEF2A significantly reduced hyperglycemia-induced CF proliferation and migration, myofibroblast differentiation, matrix metalloproteinase (MMP) activities, and collagen production. Furthermore, MEF2A inhibition attenuated HG-induced activation of the mitogen-activated protein kinase (MAPK), Akt, and TGF-β1/Smad signaling pathways. For in vivo analysis in a mouse model, type-1 diabetes was induced by streptozotocinand MEF2A expression was knocked down by myocardial injection with lentivirus carrying shRNA-MEF2A. Cardiac function was assessed by echocardiography. Total collagen deposition was assessed by Masson's trichrome and Picrosirius red staining. Knockdown of MEF2A ameliorated diabetes-induced cardiac dysfunction and collagen deposition. Our study suggests that inhibition of MEF2A could alleviate HG-induced extracellular matrix accumulation by blocking the activation of Akt and TGF-β1/Smad signaling pathway in CFs. Thus, inhibition of MEF2A has therapeutic potential in the treatment of diabetic-induced cardiac remodeling.