title: Vascular superoxide dismutase deficiency impairs endothelial vasodilator function through direct inactivation of nitric oxide and increased lipid peroxidation.
abstract: Nitric oxide (NO) and superoxide are both constitutive products of the endothelium. Because NO is readily inactivated by superoxide, the bioactivity of endothelium-derived NO (EDNO) is dependent on local activity of superoxide dismutase (SOD). We examined the effects of chronic inhibition of copper-zinc SOD (CuZnSOD) using a rat model of dietary copper restriction. Male weanling Sprague-Dawley rats were fed a Cu-deficient diet and received either no Cu replacement (Cu-deficient) or Cu in the drinking water (Cu-sufficient). Compared with Cu-sufficient animals, Cu-deficiency was associated with a 68% reduction in CuZnSOD activity and a 58% increase in vascular superoxide as estimated by lucigenin chemiluminescence (both P < .05). Compared with Cu-sufficient animals, arterial relaxation in the thoracic aorta from Cu-deficient animals was 10-fold less sensitive to acetylcholine, a receptor-dependent EDNO agonist, but only 1.5-fold less sensitive to A23187, a receptor-independent EDNO agonist, and only 1.25-fold less sensitive to authentic NO (all P < .05). In contrast, acute inhibition of CuZnSOD with 10 mM diethyldithiocarbamate produced a more uniform reduction in sensitivity to acetylcholine (8-fold), A23187 (10-fold), and NO (4-fold; all P < .001). Cu-deficient animals demonstrated a 2.5-fold increase in plasma-esterified F2-isoprostanes, a stable marker of lipid peroxidation, that correlated inversely with arterial relaxation to acetylcholine (R = -.83; P < .0009) but not A23187 or authentic NO. From these findings, we conclude that chronic inhibition of CuZnSOD inhibits EDNO-mediated arterial relaxation through two mechanisms, one being direct inactivation of NO and the other being lipid peroxidation that preferentially interrupts receptor-mediated stimulation of EDNO.
authors.affiliation: Evans Memorial Department of Medicine, Boston University School of Medicine, Massachusetts 02118, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Lynch
authors.forename: B
authors.initials: B
authors.lastname: Frei
authors.forename: J D
authors.initials: JD
authors.lastname: Morrow
authors.forename: L J
authors.initials: LJ
authors.lastname: Roberts
authors.forename: A
authors.initials: A
authors.lastname: Xu
authors.forename: T
authors.initials: T
authors.lastname: Jackson
authors.forename: R
authors.initials: R
authors.lastname: Reyna
authors.forename: L M
authors.initials: LM
authors.lastname: Klevay
authors.forename: J A
authors.initials: JA
authors.lastname: Vita
authors.forename: J F
authors.initials: JF
authors.lastname: Keaney
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000503:physiopathology; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000008:administration & dosage / Q000172:deficiency*; D004050:Ditiocarb / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology; D007476:Ionophores / Q000494:pharmacology; D015227:Lipid Peroxidation; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000502:physiology; D013481:Superoxides / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D002614:Chelating Agents; D007476:Ionophores; D013481:Superoxides; D009569:Nitric Oxide; D000001:Calcimycin; D003300:Copper; D004050:Ditiocarb; D013482:Superoxide Dismutase; D000109:Acetylcholine; D002118:Calcium