Critical Role for Copper/Zinc–Superoxide Dismutase in Preventing Spontaneous Intracerebral Hemorrhage During Acute and Chronic Hypertension in Mice

Backgrounds and Purpose— Superoxide is associated with spontaneous intracerebral hemorrhage (ICH) during hypertension. The goal of this study was to test the hypothesis that changes in superoxide, in genetically altered mice with deletion and overexpression of copper/zinc–superoxide dismutase (SOD1), modulate susceptibility to ICH. Methods— Chronic hypertension was produced by infusion of angiotensin II and an inhibitor of nitric oxide synthase in drinking water in SOD1 transgenic (SOD1Tg) mice, SOD1-deficient (SOD1 −/− ) mice, and their respective wild-type littermates. Acute hypertension was produced by daily injections of angiotensin II in some mice with chronic hypertension to produce ICH. We evaluated susceptibility to ICH, oxidative stress (superoxide, NAD[P]H oxidase activity, SOD activity), gene expression, and activity of matrix metalloproteinases. Results— Incidence, size, and number of ICHs were reduced in SOD1Tg mice and were increased in SOD1 −/− mice compared with their wild-type littermates. Levels of superoxide increased in the brain even before developing ICH in wild-type littermates, whereas levels of superoxide remained low in SOD1Tg mice. Changes in level of matrix metalloproteinase-9 paralleled oxidative stress in SOD1Tg mice and wild-type littermates. Moreover, levels of superoxide and matrix metalloproteinase-9 were greater in SOD1 −/− mice than wild-type littermates after induction of ICH. Active matrix metalloproteinases colocalized on cerebral vessels that appeared to lead toward regions with ICH. Conclusions— These results suggest that superoxide contributes to the pathogenesis of spontaneous ICH, possibly through activation of matrix metalloproteinase-9, and that SOD1 protects against spontaneous ICH during hypertension.