Angiotensin II induces endothelial xanthine oxidase activation: role for endothelial dysfunction in patients with coronary disease.
OBJECTIVE
Xanthine oxidase (XO), a major source of superoxide, has been implicated in endothelial dysfunction in atherosclerosis. Mechanisms, however, leading to endothelial XO activation remain poorly defined. We tested the effect of angiotensin II (Ang II) on endothelial XO and its relevance for endothelial dysfunction in patients with coronary disease.


RESULTS
XO protein levels and XO-dependent superoxide production were determined in cultured endothelial cells in response to Ang II. In patients with coronary disease, endothelium-bound XO activity as determined by ESR spectroscopy and endothelium-dependent vasodilation were analyzed before and after 4 weeks of treatment with the AT1-receptor blocker losartan, the XO inhibitor allopurinol, or placebo. Ang II substantially increased endothelial XO protein levels and XO-dependent superoxide production in cultured endothelial cells, which was prevented by NAD(P)H-oxidase inhibition. In vivo, endothelium-bound XO activity was reduced by losartan and allopurinol, but not placebo therapy in patients with coronary disease. XO inhibition with oxypurinol improved endothelium-dependent vasodilation before, but not after losartan or allopurinol therapy.


CONCLUSIONS
These findings suggest a novel mechanism whereby Ang II promotes endothelial oxidant stress, ie, by redox-sensitive XO activation. In patients with coronary disease, losartan therapy reduces endothelium-bound XO activity likely contributing to improved endothelial function.
Landmesser
Ulf
U
Medizinische Hochschule Hannover, Abteilung Kardiologie und Angiologie, Carl Neuberg Str.130625 Hannover, Germany. Landmesser.Ulf@MH-Hannover.DE
Spiekermann
Stephan
S
Preuss
Christoph
C
Sorrentino
Sajoscha
S
Fischer
Dieter
D
Manes
Costantina
C
Mueller
Maja
M
Drexler
Helmut
H
D000368:Aged; D000493:Allopurinol / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D003326:Coronary Circulation; D003327:Coronary Disease / Q000201:enzymology / Q000503:physiopathology*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000201:enzymology / Q000503:physiopathology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D019255:NADPH Oxidases / Q000378:metabolism; D010117:Oxypurinol / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*
D047228:Angiotensin II Type 1 Receptor Blockers; D004791:Enzyme Inhibitors; D013481:Superoxides; D000804:Angiotensin II; D000493:Allopurinol; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; D010117:Oxypurinol; D019808:Losartan