Journal
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
Volume 292, Issue 3, Pages E756-E764Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00570.2006
Keywords
ghrelin; nitric oxide; endothelium
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Funding
- Intramural NIH HHS Funding Source: Medline
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Ghrelin is an orexigenic peptide hormone secreted by the stomach. In patients with metabolic syndrome and low ghrelin levels, intra-arterial ghrelin administration acutely improves their endothelial dysfunction. Therefore, we hypothesized that ghrelin activates endothelial nitric oxide synthase ( eNOS) in vascular endothelium, resulting in increased production of nitric oxide ( NO) using signaling pathways shared in common with the insulin receptor. Similar to insulin, ghrelin acutely stimulated increased production of NO in bovine aortic endothelial cells ( BAEC) in primary culture ( assessed using NO-specific fluorescent dye 4,5-diaminofluorescein) in a time-and dose-dependent manner. Production of NO in response to ghrelin ( 100 nM, 10 min) in human aortic endothelial cells was blocked by pretreatment of cells with N-G-nitro-L-arginine methyl ester ( nitric oxide synthase inhibitor), wortmannin [phosphatidylinositol (PI) 3-kinase inhibitor], or (D-Lys(3))-GHRP-6 ( selective antagonist of ghrelin receptor GHSR-1a), as well as by knockdown of GHSR-1a using small-interfering ( si) RNA ( but not by mitogen/extracellular signal-regulated kinase inhibitor PD-98059). Moreover, ghrelin stimulated increased phosphorylation of Akt (Ser(473)) and eNOS ( Akt phosphorylation site Ser(1179)) that was inhibitable by knockdown of GHSR-1a using siRNA or by pretreatment of cells with wortmannin but not with PD-98059. Ghrelin also stimulated phosphorylation of mitogen-activated protein ( MAP) kinase in BAEC. However, unlike insulin, ghrelin did not stimulate MAP kinase-dependent secretion of the vasoconstrictor endothelin-1 from BAEC. We conclude that ghrelin has novel vascular actions to acutely stimulate production of NO in endothelium using a signaling pathway that involves GHSR-1a, PI3-kinase, Akt, and eNOS. Our findings may be relevant to developing novel therapeutic strategies to treat diabetes and related diseases characterized by reciprocal relationships between endothelial dysfunction and insulin resistance.
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