Endothelin-1 in humans is increased by oxygen-derived radicals ex vivo and in vivo.
Endothelin-1, angiotensin II, and oxygen-derived radicals are pivotal factors in the development and progression of atherosclerosis. In vitro studies suggest that generation of oxygen-derived radicals by angiotensin II is an important mechanism increasing endothelin-1 synthesis, which consecutively may trigger effects such as cell proliferation and hypertrophy. The aim of this study was to confirm our previous data in an ex vivo and an in vivo setting. Explanted segments of internal mammary arteries were analyzed for big endothelin-1 expression following incubation with xanthine oxidase, angiotensin II, superoxide dismutase, and catalase to stimulate or to specifically inactivate oxygen-derived radicals. Endothelin-1 concentrations were determined by immunostaining and enzyme-linked immunosorbent assay. Further, oxypurinol was given to patients undergoing coronary angioplasty, a procedure known to increase plasma endothelin-1 concentrations. Angiotensin II and xanthine oxidase dose-dependently increased big endothelin-1 concentrations (p < .01 and p < .0001); the effects could be inhibited by coincubation with superoxide dismutase and catalase as determined by both semiquantitative immunofluorescence and enzyme-linked immunosorbent assay (p < .01). Patients undergoing coronary angioplasty exhibited significantly elevated big endothelin-1 concentrations 60 minutes after angioplasty (p = .03); in patients also receiving oxypurinol immediately after angioplasty, big endothelin-1 concentrations decreased (p = .001). Our results may explain the association between elevated angiotensin II levels, increased oxidative stress, and increased endothelin-1 concentrations in atherosclerosis. The data therefore support the concept that oxygen-derived free radicals stimulate the release of endothelin-1, which subsequently induces effects such as proliferation and enhanced agonist-induced vasoconstriction, previously attributed directly to angiotensin II.
Knappe
Dorit
D
Department of Cardiology, University Hospital Hamburg Eppendorf, Hamburg, Germany.
Sill
Bjoern
B
Tharun
Bjoern
B
Koester
Ralf
R
Baldus
Stephan
S
Muenzel
Thomas
T
Meinertz
Thomas
T
Kähler
Jan
J
D000804:Angiotensin II / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism; D019332:Endothelin-1 / Q000097:blood / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008323:Mammary Arteries / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress; D010117:Oxypurinol / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D019820:Xanthine / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism
D019332:Endothelin-1; D016166:Free Radical Scavengers; D005609:Free Radicals; D017382:Reactive Oxygen Species; D000804:Angiotensin II; D019820:Xanthine; D002374:Catalase; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; D010117:Oxypurinol