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Titre du document / Document title

Role of the Lysine-Specific Demethylase 1 in the Proinflammatory Phenotype of Vascular Smooth Muscle Cells of Diabetic Mice

Auteur(s) / Author(s)

REDDY Marpadga A. (1) ; VILLENEUVE Louisa M. (1 2) ; MEI WANG (1) ; LANTING Linda (1) ; NATARAJAN Rama (1 2) ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

(1) Department of Diabetes, Beckman Research Institute of City of Hope, Duarte, Calif, ETATS-UNIS
(2) Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, Calif, ETATS-UNIS

Résumé / Abstract

-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 inflammatory gene expression and enhanced VSMC-monocyte binding in nondiabetic VSMCs. In contrast, overexpression of LSD1 in diabetic db/db VSMCs inhibited their enhanced inflammatory gene expression. These results demonstrate novel functional roles for LSD1 and H3K4 methylation in VSMCs and inflammation. Dysregulation of their actions may be a major mechanism for vascular inflammation and metabolic memory associated with diabetic complications.

Revue / Journal Title

Circulation research    ISSN  0009-7330   CODEN CIRUAL 

Source / Source

2008, vol. 103, no6, pp. 615-623 [9 page(s) (article)] (40 ref.)

Langue / Language

Anglais

Editeur / Publisher

Lippincott Williams & Wilkins, Hagerstown, MD, ETATS-UNIS  (1953) (Revue)

Mots-clés anglais / English Keywords

Rodentia

;

Vascular disease

;

Cardiovascular disease

;

Endocrinopathy

;

Aminoacid

;

Vertebrata

;

Mouse

;

Atherosclerosis

;

Diabetes mellitus

;

Mammalia

;

Circulatory system

;

Histone

;

Smooth muscle

;

Phenotype

;

Inflammation

;

Lysine

;

Mots-clés français / French Keywords

Rodentia

;

Pathologie des vaisseaux sanguins

;

Pathologie de l'appareil circulatoire

;

Endocrinopathie

;

Aminoacide

;

Vertebrata

;

Souris

;

Athérosclérose

;

Diabète

;

Mammalia

;

Appareil circulatoire

;

Histone

;

Muscle lisse

;

Phénotype

;

Inflammation

;

Lysine

;

Mots-clés espagnols / Spanish Keywords

Rodentia

;

Vaso sanguíneo patología

;

Aparato circulatorio patología

;

Endocrinopatía

;

Aminoácido

;

Vertebrata

;

Ratón

;

Ateroesclerosis

;

Diabetes

;

Mammalia

;

Aparato circulatorio

;

Histona

;

Músculo liso

;

Fenotipo

;

Inflamación

;

Lisina

;

Mots-clés d'auteur / Author Keywords

atherosclerosis

;

diabetes

;

histone modifications

;

inflammation vascular smooth muscle cells

;

Localisation / Location

INIST-CNRS, Cote INIST : 7216, 35400018560525.0120

Nº notice refdoc (ud4) : 20679926



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