Abstract 1465: Increased Systemic Ghrelin Levels are Associated with Improved Endothelial Function and Decreased Vascular NAD(P)H Oxidase Activity in Atherosclerotic Patients.
Ghrelin is a novel peptide involved in appetite control. It’s levels are increased in fasting and recent studies have shown that it has anti-inflammatory effects in endothelial cells and that it’s receptors are expressed in human vasculature. The effects of ghrelin in human vasculature are unknown. We aimed to investigate the relationships between fasting ghrelin plasma levels and endothelial function and vascular oxidative stress, as well as direct effects of ghrelin on those parameters in isolated human arteries in vitro.
Methods: Plasma was obtained from 70 patients undergoing CABG surgery, following 20 hour fasting prior to pre-medication. Segments of saphenous vein and mammary artery were obtained. Endothelial function was determined ex vivo as acetylcholine (ACh) induced endothelium dependent vasorelaxations. Superoxide production (O2-.)and NADPH oxidase activity were measured by 5uM lucigenin. Effects of increasing concentrations of ghrelin (10pg/ml-1ng/ml) were studied in intact segments of IMA, showing endothelial dysfunction (AChmax < 20%). Fasting ghrelin plasma levels were measured by RIA.
Results: Ghrelin plasma levels were associated with endothelium dependent vasorelaxations (AChmax: R=+0.5; p<0.001; n=70) but not with endothelium independent vasorelaxations (SNPmax: R=−0.08; p>0.05; n=70). Ghrelin levels remain independent predictor of endothelial function after accounting for major risk factors. Ghrelin plasma levels were also correlated with vascular O2-. production (R=−0.45; p<0.01; n=70) and NADPH oxidase activity (R=−0.45; p<0.01; n=70). Interestingly pre-incubation of human internal mammary artery segments in vitro with ghrelin (500pg/ml) caused improvement of endothelium dependent relaxations (AChmax: 39.5±8% vs. 16.0±5%; n=6); inhibition of vascular O2-. (11.3±2.8 vs 24.9±4 RLU/sec/mg) and NADPH oxidase activity (529±120 vs 1434±200 RLU/sec/mg). These effects were concentration dependent. Ghrelin shows no direct superoxide scavenging effects in xanthine-xanthine oxidase O2-. generating system. Ghrelin effects were in turn partially (by 55%) reversed by L-NAME.
Conclusions: Ghrelin may be an important novel regulator of endothelial function and vascular oxidative stress in atherosclerosis.