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This Article Full Text Full Text (PDF) Supplemental Information All Versions of this Article: 293/6/R2218    most recent 00295.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Mundy, A. L. Articles by Barton, M. PubMed PubMed Citation Articles by Mundy, A. L. Articles by Barton, M.

INFLAMMATION AND CYTOKINES

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, O₂^–, and H₂O₂ 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