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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

International Journal of Biochemistry and Cell Biology 69: 52-61

ISSN/ISBN: 1357-2725

PMID: 26482596

DOI: 10.1016/j.biocel.2015.10.012

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.

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Accession: 058119045

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