Endothelin stimulates vascular hydroxyl radical formation: effect of obesity

Molecular Internal Medicine, Medical Policlinic, Department of Internal Medicine, University Hospital Zurich, Zürich, Switzerland Submitted 27 April 2007 ; accepted in final form 19 September 2007 Reactive oxygen species (ROS) and endothelin-1 (ET-1) contribute to vascular pathophysiology in obesity. In this context, whether ET-1 modulates hydroxyl radical ( OH) formation and the function of ROS/ OH in obesity is not known. In the present study, formation and function of ROS, including OH, were investigated in the aorta of lean and leptin-deficient obese ob/ob mice. Hydroxyl radical formation was detected ex vivo using terephthalic acid in intact aortic rings and the involvement of ROS in ET-1-mediated vasoreactivity was analyzed using the antioxidant EPC-K1, a combination of -tocopherol and ascorbic acid. Generation of either OH, O 2 – , and H 2 O 2 was strongly inhibited by EPC-K1 (all P < 0.05). In obese mice, basal vascular OH formation and ROS activity were reduced by 3-fold and 5-fold, respectively ( P < 0.05 vs. lean). ET-1 markedly enhanced OH formation in lean (6-fold, P < 0.05 vs. untreated) but not in obese mice. Obesity increased ET-1-induced contractions ( P < 0.05 vs. lean), and ROS scavenging further enhanced the response ( P < 0.05 vs. untreated). Exogenous ROS, including OH caused stronger vasodilation in obese animals ( P < 0.05 vs. lean), whereas endothelium-dependent relaxation was similar between lean and obese animals. In conclusion, we present a sensitive method allowing ex vivo measurement of vascular OH generation and provide evidence that ET-1 regulates vascular OH formation. The data indicate that in obesity, vascular formation of ROS, including OH is lower, whereas the sensitivity to ROS is increased, suggesting a novel and important role of ROS, including OH in the regulation of vascular tone in disease status associated with increased body weight. oxidative stress; acetylcholine; vasoconstriction; murine; ob/ob ; terephthalic acid; vitamin E; vitamin C Address for reprint requests and other correspondence: M. Barton, Medical Policlinic, Dept. of Internal Medicine, Univ. Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland (e-mail: barton{at}usz.ch )