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Glucagon-like Peptide-1 Receptor Agonist Liraglutide Inhibits Endothelin-1 in Endothelial Cell by Repressing Nuclear Factor-Kappa B Activation

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Abstract

Purpose

The increase in endothelin-1 (ET-1) and the decrease in endothelial nitric oxide synthase (eNOS) both induce vasoconstriction and lead to molecular changes associated with diabetes mellitus and atherosclerosis. Glucagon-like peptide-1 (GLP-1) activation stimulates insulin secretion and may prevent atherosclerosis by increasing eNOS synthesis. However, there is paucity of information on the effect of GLP-1 activation on ET-1 expression. This study was conducted to address this issue.

Methods and Results

Human umbilical vein endothelial cells (HUVECs) were incubated with different concentrations of liraglutide, a GLP-1 agonist, and the expression of ET-1 and eNOS and activity of NF-κB were measured. Liraglutide, in a concentration-dependent manner, was observed to promote eNOS expression and to inhibit ET-1 expression both at mRNA and protein levels. Liraglutide also inhibited NF-κB phosphorylation and its translocation from cytoplasm to the nucleus. To ascertain the role of NF-κB activation in the altered expression of ET-1 and eNOS, we treated HUVECs with phorbol 12-myristate 13-acetate (PMA). PMA activated NF-κB and reversed the effects of liraglutide on eNOS and ET-1 expression. The effects of PMA on eNOS and ET-1 expression were reproduced in experiments wherein cells were treated with TNF-α. Further, we measured the generation of IL-6, apowerful pro-inflammatory molecule released by endothelial cells, as a measure of cellular function. PMA increased IL-6 generation, and this effect was blocked by liraglutide.

Conclusions

Our observations suggest liraglutide suppresses ET-1 expression by inhibiting the phosphorylation of NF-κB. This mechanism may underlie the potential anti-atherosclerotic effects of GLP-1 agonists. Of note, these effects of liraglutide were seen in an in vitro setting wherein cellular glucose concentrations were elevated.

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Abbreviations

GLP-1:

Glucagon-like peptide-1

GLP-1R:

Glucagon-like peptide-1 receptor

ET-1:

Endothelin-1

eNOS:

Endothelial nitric oxide synthase

NF-κB:

Nuclear factor-KappaB

HUVECs:

Human umbilical vein endothelial cells

PMA:

Phorbol 12-myristate 13-acetate

DPP4:

Dipeptidyl peptidase-4

IκBα:

Inhibitor of kappa B alpha

IL-6:

Interleukin-6

TNF-α:

Tumor necrosis factor-alpha

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Acknowledgments

This study was supported by funds from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development, Washington, DC. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China

    Yao Dai & Mingwei Chen

  2. Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    Yao Dai & Jawahar L. Mehta

  3. Cardiovascular Division, UAMS, Little Rock, AR, 72212, USA

    Jawahar L. Mehta

Authors
  1. Yao Dai
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  2. Jawahar L. Mehta
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  3. Mingwei Chen
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Correspondence to Jawahar L. Mehta or Mingwei Chen.

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Dai, Y., Mehta, J.L. & Chen, M. Glucagon-like Peptide-1 Receptor Agonist Liraglutide Inhibits Endothelin-1 in Endothelial Cell by Repressing Nuclear Factor-Kappa B Activation. Cardiovasc Drugs Ther 27, 371–380 (2013). https://doi.org/10.1007/s10557-013-6463-z

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  • DOI: https://doi.org/10.1007/s10557-013-6463-z

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