Inhibition of MEF2A prevents hyperglycemia-induced extracellular matrix accumulation by blocking Akt and TGF-β1/Smad activation in cardiac fibroblasts
Inhibition of MEF2A prevents hyperglycemia-induced extracellular matrix accumulation by blocking Akt and TGF-β1/Smad activation in cardiac fibroblasts
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DOI：
10.1016/j.biocel.2015.10.012
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发表时间：
2015-12-01
影响因子：
4
通讯作者：
Zhang, Mingxiang
中科院分区：
文献类型：
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作者：
Chen, Xueying;Liu, Guoliang;Zhang, Mingxiang
肌细胞增强因子2A(MEF2A)参与肌肉特异性和/或生长因子相关的转录，参与细胞的生长、存活和凋亡。为了评估该转录因子在糖尿病心脏成纤维细胞(CFs)中的作用，我们进行了一系列体外和体内实验。我们使用短发夹状RNA(ShRNA)在体外抑制CFs中MEF2A的表达。抑制MEF2A可显著降低高血糖诱导的CFs增殖和迁移、肌成纤维细胞分化、基质金属蛋白酶(MMPs)活性和胶原生成。此外，抑制MEF2A可减弱HG诱导的丝裂原活化蛋白激酶(MAPK)、Akt和转化生长因子-β1/Smad信号通路的激活。在小鼠模型的体内分析中，用链脲佐菌素诱导1型糖尿病，并通过心肌注射携带shRNA-MEF2A的慢病毒下调MEF2A的表达。超声心动图评价心功能。用Masson‘s三色法和天狼星红染色检测总胶原沉积。敲除MEF2A可改善糖尿病引起的心功能障碍和胶原沉积。我们的研究提示，抑制MEF2A可能通过阻断Akt和转化生长因子-β1/Smad信号通路而减轻HG诱导的细胞外基质积聚。因此，抑制MEF2A在治疗糖尿病心脏重塑方面具有潜在的治疗潜力。(C)2015爱思唯尔有限公司。保留所有权利。
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-beta 1/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-beta 1/Smad signaling pathway in CFs. Thus, inhibition of MEF2A has therapeutic potential in the treatment of diabetic-induced cardiac remodeling. (C) 2015 Elsevier Ltd. All rights reserved.