The Effects of GLP-1 Receptor Agonists on Endothelial Function: Do They
Function Directly or Indirectly?

Masataka Kudo; Akiko Saito-Hakoda; Ken Matsuda; Kyoko Shimizu; Ikuko Sato; Akira Uruno; Takeo Yoshikawa; Yuko Iki; Kaori Sugawara; Naotaka Kogure; Takako Saito-Ito; Sadayoshi Ito; Akira Sugawara

ISSN: 2161-0479

Journal of Autacoids and Hormones

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The Effects of GLP-1 Receptor Agonists on Endothelial Function: Do They Function Directly or Indirectly?

Masataka Kudo¹, Akiko Saito-Hakoda², Ken Matsuda¹, Kyoko Shimizu², Ikuko Sato², Akira Uruno³, Takeo Yoshikawa⁴, Yuko Iki², Kaori Sugawara², Naotaka Kogure², Takako Saito-Ito² , Sadayoshi Ito¹ and Akira Sugawara^2*
¹Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
²Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Japan
³Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
⁴Department of Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
Corresponding Author :	Akira Sugawara Department of Molecular Endocrinology Tohoku University Graduate School of Medicine Seiryo-machi, Aoba-ku Sendai, 980-8575 Japan Tel: +81-22-717-7483 Fax: +81-22-717-8083 E-mail: akiras2i@med.tohoku.ac.jp
Received December 27, 2012; Accepted December 28, 2012; Published December 29, 2012
Citation: Kudo M, Saito-Hakoda A, Matsuda K, Shimizu K, Sato I, et al. (2013) The Effects of GLP-1 Receptor Agonists on Endothelial Function: Do They Function Directly or Indirectly? Autacoids 2:e121. doi: 10.4172/2161-0479.1000e121
Copyright: © 2013 Kudo M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Glucagon-like peptide 1 (GLP-1) receptor agonists, as well as dipeptidyl peptidase-4 inhibitors, have recently been widely used as therapeutics of type 2 diabetes [1]. According to the accumulation of clinical experience, cardiovascular protective effects of GLP-1 receptor agonists have been focused [2,3]. Although these effects may partly be due to their indirect glucose-lowering and weight-losing effects [4], recent evidence has indicated their direct effects on endothelium.

GLP-1 receptor, a seven-transmembrane G-protein coupled receptor consists of 463 amino acids, is not only expressed in pancreatic islets, but also in broad range of organs including endothelium [5]. A GLP-1 receptor agonist liraglutide has been demonstrated to stimulate endothelial nitric oxide (NO) synthase (eNOS) phosphorylation at Ser-1177/NO production via AMP-activated protein kinase (AMPK) activation in human umbilical vein endothelial cells (HUVEC) [6]. Another GLP-1 receptor agonist exenatide also induced eNOS phosphorylation at Ser-1177 in HUVEC, indicating that the effect is mediated via GLP-1 receptor [7]. However, GLP-1(9-36), which has a weak affinity for GLP-1 receptor, also stimulated eNOS phosphorylation at Ser-1177 in HUVEC [7]. Additionally, NO-mediated vasodilatory effects by GLP-1 and GLP-1(9-36) were maintained in Glp-1r^-/- mice [8]. Therefore, the existence of GLP-1 receptor-independent pathway for eNOS phosphorylation/NO production is also speculated.
Regarding the signal transduction of GLP-1-mediated eNOS phosphorylation/NO production, involvement of protein kinase A (PKA) has also been demonstrated in bovine aortic EC [9]. Recently, GLP-1 receptor/cyclic AMP/PKA/liver kinase B1 (LKB1)/AMPK/eNOS cascade has been proposed for the GLP-1-stimulated NO production [10]. The phosphoinositide 3-kinase (PI3K)/Akt cascade is also recognized as an important pathway for eNOS phosphorylation [11]. Although exenatide has been shown to induce eNOS phosphorylation at Ser-1177 via both PKA and PI3K/Akt pathways in human coronary artery EC [12], the significance of PI3K/Akt cascade in the GLP-1- mediated NO production remains uncertain. We therefore performed DNA microarray analyses to examine the effect of liraglutide on human coronary artery EC gene expression. Interestingly, we observed that liraglutide significantly up-regulated (3.2-fold) the expression of p87 (PIKAP), which is a novel regulatory subunit of PI3K p110gamma [13] (Kudo et al. unpublished data). Further studies are needed to define the importance of PI3K/Akt pathway and its crosstalk with PKA/LKB1/ AMPK cascade in the GLP-1-mediated eNOS phosphorylation/NO production.