Homocysteine-induced oxidative stress through TLR4/NF-κB/DNMT1-mediated LOX-1 DNA methylation in endothelial cells

• Published in: Molecular medicine reports Vol. 16; no. 6; pp. 9181 - 9188
• Main Authors: Ma, Sheng-Chao, Hao, Yin-Ju, Jiao, Yun, Wang, Yan-Hua, Xu, Ling-Bo, Mao, Cai-Yan, Yang, Xiao-Ling, Yang, An-Ning, Tian, Jue, Zhang, Ming-Hao, Jin, Shao-Ju, Xu, Hua, Jiang, Yi-Deng, Zhang, Hui-Ping
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.12.2017; Spandidos Publications UK Ltd
• Subjects: Arteriosclerosis; Bioengineering; Biomarkers; Cardiovascular disease; Cells, Cultured; Dehydrogenases; Deoxyribonucleic acid; DNA; DNA (Cytosine-5-)-Methyltransferase 1 - metabolism; DNA Methylation; DNA methyltransferase; DNMT1 protein; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Gene expression; Gene Expression Regulation; Homocysteine; Homocysteine - metabolism; Homocysteine - pharmacology; Humans; Hydrogen Peroxide; Lectins; Lipids; Lipoproteins, LDL; Low density lipoprotein; Low density lipoprotein receptors; LOX-1 protein; Malondialdehyde; NF-kappa B - metabolism; NF-κB protein; Oxidative Stress; Pathogenesis; Polymerase chain reaction; Pyrrolidine dithiocarbamate; Receptor density; Scavenger Receptors, Class E - genetics; Studies; Superoxide dismutase; Superoxide Dismutase - metabolism; TLR4 protein; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; toll-like receptor/nuclear factor-κB/DNA methyltransferase 1; Toll-like receptors; Vitamin B
• ISSN: 1791-2997; 1791-3004
• DOI: 10.3892/mmr.2017.7753

Atherosclerosis (AS) is a progressive disease of multifactorial origin, which occurs in response to endothelial injury. Increased homocysteine (Hcy) is considered a major cause of endothelial dysfunction, oxidative stress and DNA methylation; however, the mechanisms remain to be fully elucidated. The aim of the present study was to investigate whether Hcy causes injury to endothelial cells (ECs) by the effect of lectin-like oxidized-low density lipoprotein receptor-1 (LOX-1) DNA methylation through toll-like receptor 4(TLR4)/nuclear factor (NF)-κB/DNA methyltransferase (DNMT)1. The ECs were treated with different concentrations of Hcy, and it was found that Hcy promoted the expression of TLR4, leading to EC injury. The effect of oxidative stress was analyzed by measuring superoxide dismutase, malondialdehyde and hydrogen peroxide in the ECs. In addition, the association between NF-κB and DNMT1 was examined by treatment of the ECs with pyrrolidine dithiocarbamate (PDTC). The results suggested that Hcy induced LOX-1 DNA hypomethyaltion to promote the expression levels of LOX-1. Taken together, Hcy injured the ECs through the effect of methylation and trans-sulfuration metabolism of LOX-1 through TLR4/NF-κB/DNMT1. Following injury to the ECs, lipids, particularly ox-LDL, accumulated in the sub-endothelial layer to promote the formation of AS.