Critical role for CuZn-superoxide dismutase in preventing angiotensin II-induced endothelial dysfunction.
The goal of the present study was to test the hypothesis that the CuZn isoform of superoxide dismutase (CuZnSOD) protects against angiotensin II (Ang II)-induced endothelial dysfunction. Vascular responses of carotid arteries from control, CuZnSOD-deficient (CuZnSOD(+/-)), and CuZnSOD transgenic mice were examined in vitro after overnight incubation with either vehicle or Ang II (1 or 10 nmol/L). In control mice, acetylcholine produced concentration-dependent relaxation that was not affected by 1 nmol/L Ang II. In contrast, relaxation to acetylcholine in arteries from CuZnSOD+/- mice was markedly and selectively attenuated after incubation with 1 nmol/L Ang II (eg, 100 micromol/L acetylcholine produced 93+/-6% and 44+/-15% relaxation in vehicle- and Ang II-treated arteries, respectively). A higher concentration of Ang II (10 nmol/L) selectively impaired relaxation to acetylcholine in arteries from control mice (eg, 100 micromol/L acetylcholine produced 96+/-4% and 45+/-7% relaxation in vehicle- and Ang II-treated vessels, respectively). In contrast, 10 nmol/L Ang II had no effect on responses to acetylcholine in carotid arteries from CuZnSOD transgenic mice (or in control mice treated with the superoxide scavenger Tiron [1 mmol/L]). Superoxide levels in control mice were higher in aorta treated with Ang II than with vehicle and were markedly reduced in CuZnSOD transgenic mice. These findings provide the first direct evidence that CuZnSOD limits Ang II-mediated impairment of endothelial function and that loss of 1 copy of the CuZnSOD gene is sufficient to enhance Ang II-induced vascular dysfunction.
Didion
Sean P
SP
Department of Internal Medicine, Cardiovascular Center, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. sean-didion@uiowa.edu
Kinzenbaw
Dale A
DA
Faraci
Frank M
FM
D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology*; D018628:Gene Dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009994:Osmolar Concentration; D013482:Superoxide Dismutase / Q000235:genetics / Q000502:physiology*; D014664:Vasodilation / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D014665:Vasodilator Agents; D000804:Angiotensin II; D013482:Superoxide Dismutase; D000109:Acetylcholine