Glucose-independent persistence of PAI-1 gene expression and H3K4 tri-methylation in type 1 diabetic mouse endothelium

Implication in metabolic memory

Fumihiko Takizawa, Shuki Mizutani, Yoshihiro Ogawa, Naoki Sawada

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Clinical trials with type 1 and type 2 diabetes have identified a phenomenon known as " metabolic memory" in which previous periods of hyperglycemia result in the long-lasting deleterious impact on cardiovascular events. Emerging evidence shows that transient hyperglycemic exposure of human endothelial cells induces histone 3 lysine 4 mono-methylation (H3K4me1) on the promoter and persistent mRNA expression of RelA and IL-8 genes, suggesting that epigenetic histone modification and chromatin structure remodeling is a key event underlying metabolic memory. This burgeoning hypothesis, however, critically remains to be tested for relevance in the disease process of diabetes in vivo, and for broader applicability to an array of genes involved in endothelial dysfunction. To address this, we used type 1 diabetes mouse model induced by streptozocin to be hyperglycemic for 8. weeks, and isolated endothelial cells that were used either freshly after isolation or after 2 to 3-week cell culture in normoglycemic conditions. mRNA expression profiling in diabetic mouse endothelial cells revealed significant and persistent up-regulation of Serpine1 encoding PAI-1, the hypo-fibrinolytic mediator leading to thrombotic diseases in diabetes, along with Rock2, Fn1 and Ccl2, whereas only Serpine 1 was persistently elevated in high glucose-treated mouse endothelial cells. Chromosome immunoprecipitation assay in type 1 diabetic mouse endothelial cells showed predominant enrichment of H3K4 tri-methylation on Serpine1 promoter, suggesting a unique epigenetic regulation in diabetic mice as opposed to high glucose-treated human ECs. Our study demonstrates the importance of combining in vivo models of diabetes with high glucose-treated cell culture to better assess the epigenetic mechanisms relevant to disease.

Original languageEnglish
Pages (from-to)66-72
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume433
Issue number1
DOIs
Publication statusPublished - Mar 29 2013
Externally publishedYes

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Methylation
Plasminogen Activator Inhibitor 1
Endothelial cells
Medical problems
Gene expression
Endothelium
Endothelial Cells
Gene Expression
Data storage equipment
Glucose
Epigenomics
Type 1 Diabetes Mellitus
Cell culture
Histones
Histone Code
Cell Culture Techniques
Genes
Messenger RNA
Chromatin Assembly and Disassembly
Chromosomes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Molecular Biology

Cite this

Glucose-independent persistence of PAI-1 gene expression and H3K4 tri-methylation in type 1 diabetic mouse endothelium : Implication in metabolic memory. / Takizawa, Fumihiko; Mizutani, Shuki; Ogawa, Yoshihiro; Sawada, Naoki.

In: Biochemical and Biophysical Research Communications, Vol. 433, No. 1, 29.03.2013, p. 66-72.

Research output: Contribution to journalArticle

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