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(Circulation. 2004;109:2221-2226.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Ghrelin Inhibits Proinflammatory Responses and Nuclear Factor-B Activation in Human Endothelial Cells

Wei Gen Li, MD, PhD; Dan Gavrila, MD; Xuebo Liu, PhD; Lixing Wang, MD, PhD; Skuli Gunnlaugsson, MD; Lynn L. Stoll, PhD; Michael L. McCormick, PhD; Curt D. Sigmund, PhD; Chaosu Tang, MD; Neal L. Weintraub, MD

From the Departments of Internal Medicine (W.G.L., D.G., X.L., S.G., L.L.S., M.L.M., C.D.S., N.L.W.) and Surgery (L.W.) and the Free Radical and Radiation Biology Program (M.L.M., N.L.W.), University of Iowa, Iowa City; Veterans Affairs Medical Center, Iowa City, Iowa (N.L.W.); and Institute of Cardiovascular Disease Research, First Hospital of Peking University, and Department of Physiology, Health Science Center of Peking University, Beijing, People’s Republic of China (C.T.).

Correspondence to Dr Neal L. Weintraub, Department of Internal Medicine, Cardiovascular Division, University of Iowa College of Medicine, E-315A1 GH, Iowa City, IA 52242. E-mail neal-weintraub{at}uiowa.edu

Received August 27, 2003; de novo received November 26, 2003; accepted January 28, 2004.

Background— Ghrelin is a novel growth hormone-releasing peptide that has been shown to improve cachexia in heart failure and cancer and to ameliorate the hemodynamic and metabolic disturbances in septic shock. Because cytokine-induced inflammation is critical in these pathological states and because the growth hormone secretagogue receptor has been identified in blood vessels, we examined whether ghrelin inhibits proinflammatory responses in human endothelial cells in vitro and after administration of endotoxin to rats in vivo.

Methods and Results— Human umbilical vein endothelial cells (HUVECs) were treated with or without tumor necrosis factor- (TNF-), and induction of proinflammatory cytokines and mononuclear cell adhesion were determined. Ghrelin (0.1 to 1000 ng/mL) inhibited both basal and TNF--induced cytokine release and mononuclear cell binding. Intravenous administration of ghrelin also inhibited endotoxin-induced proinflammatory cytokine production in rats in vivo. Ghrelin inhibited H₂O₂-induced cytokine release in HUVECs, suggesting that the peptide blocks redox-mediated cellular signaling. Moreover, ghrelin inhibited basal and TNF--induced activation of nuclear factor-B. Des-acyl ghrelin had no effect on TNF--induced cytokine production in HUVECs, suggesting that the antiinflammatory effects of ghrelin require interaction with endothelial growth hormone secretagogue receptors.

Conclusions— Ghrelin inhibits proinflammatory cytokine production, mononuclear cell binding, and nuclear factor-B activation in human endothelial cells in vitro and endotoxin-induced cytokine production in vivo. These novel antiinflammatory actions of ghrelin suggest that the peptide could play a modulatory role in atherosclerosis, especially in obese patients, in whom ghrelin levels are reduced.

Key Words: hormones, peptide • inflammation • endotoxins • monocytes • nuclear factor-B

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