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 H 2 O 2 -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.

Abstract-The role of inflammation in the pathogenesis of abdominal aortic aneurysms (AAA) is well established. The inflammatory process leads to protease-mediated degradation of the extracellular matrix and apoptosis of smooth muscle cells (SMC), which are the predominant matrix synthesizing cells of the vascular wall. These processes act in concert to progressively weaken the aortic wall, resulting in dilatation and aneurysm formation. Oxidative stress is invariably increased in, and contributes importantly to, the pathophysiology of inflammation. Moreover, reactive oxygen species (ROS) play a key role in regulation of matrix metalloproteinases and induction of SMC apoptosis. ROS may also contribute to the pathogenesis of hypertension, a risk factor for AAA. Emerging evidence suggests that ROS and reactive nitrogen species (RNS) are associated with AAA formation in animal models and in humans. Although experimental data are limited, several studies suggest that modulation of ROS production or activity may suppress AAA formation and improve experimental outcome in rodent models. Although a number of enzymes can produce injurious ROS in the vasculature, increasing evidence points toward a role for NADPH oxidase as a source of oxidative stress in the pathogenesis of AAA.

Background— Angiotensin II (Ang II) contributes to vascular pathology in part by stimulating NADPH oxidase activity, leading to increased formation of superoxide (O 2 − ). We reported that O 2 − levels, NADPH oxidase activity, and expression of the p47 phox subunit of NADPH oxidase are increased in human abdominal aortic aneurysms (AAAs). Here, we tested the hypothesis that deletion of p47 phox will attenuate oxidative stress and AAA formation in Ang II–infused apoE −/− mice. Methods and Results— Male apoE −/− and apoE −/− p47 phox −/− mice received saline or Ang II (1000 ng · kg −1 · min −1 ) infusion for 28 days, after which abdominal aortic weight and maximal diameter were determined. Aortic tissues and blood were examined for parameters of aneurysmal disease and oxidative stress. Ang II infusion induced AAAs in 90% of apoE −/− versus 16% of apo −/− p47 phox −/− mice ( P <0.05). Abdominal aortic weight (14.1±3.2 versus 35.6±9.0 mg), maximal aortic diameter (1.5±0.2 versus 2.4±0.4 mm), aortic NADPH oxidase activity, and parameters of oxidative stress were reduced in apoE −/− p47 phox −/− mice compared with apoE −/− mice ( P <0.05). In addition, aortic macrophage infiltration and matrix metalloproteinase-2 activity were reduced in apoE −/− p47 phox −/− mice compared with apoE −/− mice. Deletion of p47 phox attenuated the pressor response to Ang II; however, coinfusion of phenylephrine with Ang II, which restored the Ang II pressor response, did not alter the protective effects of p47 phox deletion on AAA formation. Conclusions— Deletion of p47 phox attenuates Ang II–induced AAA formation in apoE −/− mice, suggesting that NADPH oxidase plays a critical role in AAA formation in this model.