Protective role of manganese superoxide dismutase against angiotensin II‐induced, nox2‐dependent cerebral endothelial dysfunction

Abstract

Angiotensin II (Ang II)-induced endothelial dysfunction may involve oxidative stress and NAD(P)H oxidase. Although mitochondria is a key source of superoxide, the role of superoxide dismutase (SOD) localized in mitochondria (MnSOD) in protecting against Ang II-induced endothelial dysfunction is unknown. We tested if Ang II causes superoxide-mediated endothelial dysfunction via nox2-containing NAD(P)H oxidase, and if MnSOD protects against Ang II. Experiments were performed in cannulated, pressurized basilar artery segments from C57Bl/6, NAD(P)H oxidase (nox2) deficient, wild-type (+/+) and MnSOD deficient (+/−) mice. In C57Bl/6, Ang II treatment using osmotic minipumps (7 days, 0.28 or 1.4 mg/kg/day) reduced vasodilation to acetylcholine (ACh) when compared to vehicle (P<0.05), that was partially restored by a superoxide scavenger, Tempol. In contrast to C57Bl/6, responses to ACh were not impaired in nox2 deficient mice treated with Ang II (P>0.05), suggesting Ang II-induced vascular dysfunction is nox2-dependent. In MnSOD +/+, Ang II inhibited ACh responses by ~40%, (P<0.05). In MnSOD +/−, Ang II treatment caused greater impairment of ACh responses (by ~55–85%; P<0.05). Ang II treatment did not impair responses to nitroprusside in any group. Thus, chronic Ang II causes nox2-mediated endothelial dysfunction, and MnSOD may protect against Ang II-induced cerebral endothelial dysfunction.