Methylglyoxal-mediated alteration of gene expression in human endothelial cells

Abstract

Endothelial dysfunction is an important factor in the development of vascular diseases such as atherosclerosis, hypertension and diabetes. Methylglyoxal (MG) is a highly reactive dicarbonyl metabolite that is an extremely toxic glucose degradation product with strong oxidative activity. MG is involved in the pathogenesis of vascular complications of diabetes. Several studies have reported increased MG levels in pathology models of vascular injury. The present study investigated the genome-wide transcriptional responses of human umbilical vein endothelial cells (HUVECs) exposed to MG by microarray gene expression profiling. As a result, we identified 1,624 genes that were 1.5-fold up-or down-regulated within 12 h of MG treatment. The differentially expressed genes that were dysregulated in many biological processes included inflammatory responses, cell cycle, apoptosis, and cell adhesion. These results demonstrate the MG induced genome-wide alterations in expression profile in human endothelial cells and indicate that MG may cause cytotoxicity and tissue injury in the human endothelium. The data supports the view that MG-stimulated changes in gene expression contribute to the development of vascular disease.

Analysis of global gene expression profile of rice in response to methylglyoxal indicates its possible role as a stress signal molecule

“…Analysis of gene expression patterns revealed large-scale perturbations in the rice transcriptome upon exposure to 10 mM MG concentration affecting diverse biological processes such as, metabolism, transport, signal transduction, transcription, and translation. A similar MG-mediated genome-wide alteration in expression profile has been earlier reported in human endothelial cells as well (Lee et al, 2011 ). MG-derived modifications can be either through direct interaction with DNA and/or RNA or indirectly by modifying the activity of proteins involved in diverse biological pathways (Thornalley, 2008 ).…”

Reversible histone glycation is associated with disease-related changes in chromatin architecture

“…Interestingly, our ATAC-sequencing data shows that cells treated with MGO exhibit a general chromatin compaction compared to untreated cells, suggesting that in vivo the transition between the two glycation stages occurs more rapidly. Changes in TSS accessibility could explain the previously reported rapid changes in cellular transcriptome in response to MGO treatment 40 .…”

LR-90 prevents methylglyoxal-induced oxidative stress and apoptosis in human endothelial cells

“…Moreover, higher levels of protein-bound MGO-derived AGEs such as 5-hydro-5-methylimidazolone (MG-H1) and tetrahydropyrimidine (THP) were found in human atherosclerotic plaques that are highly associated with apoptosis and inflammatory markers [45, 46]. A recent genome wide gene expression profile studies in HUVECs showed that MGO treatment may cause cytotoxicity and tissue injury in the human endothelium by altering genes involved in apoptosis, cell cycle, cell adhesion and inflammatory responses [47]. Thus, the ability of LR-90 to prevent MGO-induced oxidative stress and apoptosis in vascular ECs may be protective against development of diabetic atherosclerosis.…”

“…In the present studies, we used 50–400 µM of MGO, and this concentration caused cell injury and apoptosis to HUVECs in a concentration-dependent manner. Similar MGO concentration ranges have been used by a number of investigators for studying MGO-induced apoptosis and other biochemical changes in ECs and other types of human cells [15, 16, 27, 30–32, 37, 39, 41, 42, 47]. …”