Endothelin stimulates vascular hydroxyl radical formation: effect of obesity.
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 alpha-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.
Mundy
Alexa L
AL
Molecular Internal Medicine, Medical Policlinic, Department of Internal Medicine, University Hospital Zurich, Zürich, Switzerland.
Haas
Elvira
E
Bhattacharya
Indranil
I
Widmer
Corinne C
CC
Kretz
Martin
M
Baumann
Karin
K
Barton
Matthias
M
D000818:Animals; D001011:Aorta / Q000378:metabolism*; D019332:Endothelin-1 / Q000378:metabolism*; D017665:Hydroxyl Radical / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction
D019332:Endothelin-1; D017382:Reactive Oxygen Species; D017665:Hydroxyl Radical