دورية
Epigenetic Modification of MicroRNA-200b Contributes to Diabetic Vasculopathy
| العنوان: | Epigenetic Modification of MicroRNA-200b Contributes to Diabetic Vasculopathy |
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| المؤلفون: | Singh, Kanhaiya, Pal, Durba, Sinha, Mithun, Ghatak, Subhadip, Gnyawali, Surya C., Khanna, Savita, Roy, Sashwati, Sen, Chandan K. |
| المصدر: | Molecular Therapy; December 2017, Vol. 25 Issue: 12 p2689-2704, 16p |
| مستخلص: | Hyperglycemia (HG) induces genome-wide cytosine demethylation. Our previous work recognized miR-200b as a critical angiomiR, which must be transiently downregulated to initiate wound angiogenesis. Under HG, miR-200b downregulation is not responsive to injury. Here, we demonstrate that HG may drive vasculopathy by epigenetic modification of a miR promoter. In human microvascular endothelial cells (HMECs), HG also lowered DNA methyltransferases (DNMT-1 and DNMT-3A) and compromised endothelial function as manifested by diminished endothelial nitric oxide (eNOS), lowered LDL uptake, impaired Matrigel tube formation, lower NO production, and compromised VE-cadherin expression. Bisulfite-sequencing documented HG-induced miR-200b promoter hypomethylation in HMECs and diabetic wound-site endothelial cells. In HMECs, HG compromised endothelial function. Methyl donor S-adenosyl-L-methionine (SAM) corrected miR-200b promoter hypomethylaton and rescued endothelial function. In vivo, wound-site administration of SAM to diabetic mice improved wound perfusion by limiting the pathogenic rise of miR-200b. Quantitative stable isotope labeling by amino acids in cell culture (SILAC) proteomics and ingenuity pathway analysis identified HG-induced proteins and principal clusters in HMECs sensitive to the genetic inhibition of miR-200b. This work presents the first evidence of the miR-200b promoter methylation as a critical determinant of diabetic wound angiogenesis. |
| قاعدة البيانات: | Supplemental Index |
Full Text Finder | تدمد: | 15250016 15250024 |
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| DOI: | 10.1016/j.ymthe.2017.09.009 |