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Titre du Document
Role of the Lysine-Specific Demethylase 1 in the Proinflammatory Phenotype of Vascular Smooth Muscle Cells of Diabetic Mice
Auteur(s)
REDDY Marpadga A. ; VILLENEUVE Louisa M. ; MEI WANG ; ...
Résumé
-Insulin resistance and type 2 diabetes are major risk factors for vascular complications. Vascular smooth muscle cells (VSMCs) derived from db/db mice, an established mouse model of type 2 diabetes, displayed enhanced inflammatory gene expression and proatherogenic responses. We examined the hypothesis that aberrant epigenetic chromatin events may the underlying mechanism for this persistent dysfunctional behavior and "memory" of the diabetic cells. Chromatin immunoprecipitation assays showed that levels of histone H3 lysine 4 dimethylation (H3K4me2), a key chromatin mark associated with active gene expression, were significantly elevated at the promoters of the inflammatory genes monocyte chemoattractant protein- 1 and interleukin-6 in dbldb VSMCs relative to db/+ cells. Tumor necrosis factor-α-induced inflammatory gene expression, H3K4me2 levels, and recruitment of RNA polymerase II at the gene promoters were also enhanced in db/db VSMCs, demonstrating the formation of open chromatin poised for transcriptional activation in diabetes. On the other hand, protein levels of lysine-specific demethylasel (LSD1), which negatively regulates H3K4 methylation and its occupancy at these gene promoters, were significantly reduced in dbldb VSMCs. High glucose (25 mmol/L) treatment of human VSMCs also increased inflammatory genes with parallel increases in promoter H3K4me2 levels and reduced LSD1 recruitment. LSD1 gene silencing with small interfering RNAs significantly increased infla
Editeur
Lippincott
Identifiant
ISSN : 0009-7330 CODEN : CIRUAL
Source
Circulation research A. 2008, vol. 103, n° 6, pp. 615-623 [9 pages] [bibl. : 40 ref.]
Langue
Anglais
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