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Novel epigenetic mechanisms involved in enhanced inflammatory gene expression in vascular smooth muscle cells derived from diabetic db/db mice and relation to diabetic memory
Author(s) -
Villeneuve Louisa M,
Reddy Marpadga A,
Lanting Linda L,
Wang Mei,
Meng Li,
Natarajan Rama
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.318.2
Subject(s) - epigenetics , inflammation , histone , dna methylation , endocrinology , gene silencing , vascular smooth muscle , histone h3 , medicine , chromatin , diabetes mellitus , biology , gene expression , microbiology and biotechnology , gene , genetics , smooth muscle
Diabetes and associated inflammation are major risk factors for vascular complications despite glycemic control, thus implicating a “diabetic memory”. However, the molecular mechanisms are unclear. We hypothesized that dysregulation of histone H3 lysine trimethylation (H3K9me3), a key repressive epigenetic chromatin mark, may lead to diabetic memory. This was tested in vascular smooth muscle cells (VSMC) derived from insulin resistant type 2 diabetic db/db mice, which exhibit persistent pro‐atherogenic and inflammatory phenotype even in normoglycemic culture. H3K9me3 levels at promoters of key inflammatory genes (ChIP assays) and protein levels of the H3K9me3 methyltransferase Suv39h1 (W. Blot) were significantly decreased in db/db VSMC relative to non‐diabetic control db/+ cells. Furthermore, db/db VSMC were hypersensitive to inflammatory stimuli (TNFα) which induced dramatic reductions in promoter H3K9me3 and occupancies of Suv39h1. Suv39H1 gene silencing in non‐diabetic VSMC increased inflammatory genes, while conversely, Suv39H1 overexpression in db/db VSMC reversed this diabetic phenotype. These novel findings demonstrate protective roles for H3K9me3 and Suv39H1 in the pre‐activated diabetic cells. Aberrant epigenetic histone methylation may be a major mechanism for diabetic memory implicated in chronic inflammation and diabetic complications. Support: NIH, Myrtle Carr Fdn