Docosahaenoic acid (DHA) exerts its anti-atherogenic effects in endothelial cells via epigenetic and transcriptional mechanisms
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Date
2022-02-02
Authors
Huang, Shiqi
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Abstract
Atherosclerosis, the main contributor to a range of cardiovascular diseases, can be regulated by various epigenetic and transcriptional mechanisms, including p38 mitogen- activated protein kinase (MAPK) and nuclear factor κB (NF-κB) signaling. Docosahexaenoic acid (DHA) is widely assumed to have atheroprotective effects but the underlying mechanisms remain largely unknown. Our laboratory previously reported that DHA activates p38 MAPK differently in growing and quiescent human endothelial cells, which represent the atherogenic and healthy states in vivo, respectively. Also, DHA can inhibit NF-κB in endothelial cells. Thus, we hypothesized that DHA may exert its atheroprotective effects in endothelial cells via epigenetic and transcriptional mechanisms involving p38 MAPK/NF-κB signaling. EA.hy926 cells were cultured on Matrigel-coated plates for growing and quiescent states and were treated with DHA and inhibitors for p38 MAPK or other enzymes downstream of p38 MAPK. The activation and/or protein levels of various cell signaling and epigenetic players were detected by Western blotting. In general, DHA was found to activate eNOS, mediate eNOS expression, regulate the transactivation of NF-κB and CREB, influence histone H3 phosphorylation, affect cell cycling, and alter cyclin D1 protein levels. Most of these effects of DHA showed concentration-, time-, and endothelial cell growth state-dependency. While 125 μM DHA may be deleterious for endothelial cells, 20 μM DHA showed potential atheroprotective effects that were superior in quiescent cells compared to growing cells. The effects of DHA likely result from the modulation of certain transcription factors such as NF-κB and histone marks, with some involvement of p38 MAPK signaling. Overall, DHA was able to exert its atheroprotective effect via epigenetic and transcriptional mechanisms. These findings may lead to further research to help refine the recommendations for DHA intake under different health conditions and identify potential therapeutic targets and/or diagnostic markers for endothelial functions and atherosclerosis.
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Keywords
DHA, Endothelial cells, epigenetic and transcriptional control, Atherosclerosis