Activation of NAD(P)H oxidase and oxidative stress precede spontaneous intracranial hemorrhage in hypertensive mice

Cardiovascular Center and Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
Journal of Cerebral Blood Flow & Metabolism (Impact Factor: 5.41). 07/2008; 28(6):1175-85. DOI: 10.1038/jcbfm.2008.7
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We have developed an experimental model of spontaneous intracranial hemorrhage (ICH) in transgenic mice expressing human renin and human angiotensinogen (R+/A+) treated with high-salt diet and N(omega)-nitro-L-arginine methyl ester (L-NAME). We investigated whether oxidative stress is associated with spontaneous ICH in R+/A+ mice. R+/A+ mice on high-salt diet and L-NAME presented neurologic signs 57+/-13 (mean+/-s.e.m.) days after the start of treatment. Intracranial hemorrhage was shown with histologic examination. Levels of superoxide in brain homogenate were significantly increased in R+/A+ mice with ICH (118+/-10 RLU per sec per mg; RLU, relative light unit) compared with age-matched control mice (19+/-1) and R+/A+ mice without ICH (53+/-3). NAD(P)H oxidase activity was significantly higher in R+/A+ mice with ICH (34,933+/-2,420 RLU per sec per mg) than in control mice (4,984+/-248) and R+/A+ mice without ICH (15,069+/-917). These results suggest that increased levels of superoxide are due, at least in part, to increased NAD(P)H oxidase activity. Increased NAD(P)H oxidase activity preceded signs of ICH, and increased further when R+/A+ mice developed ICH. These findings suggest that oxidative stress may contribute to spontaneous ICH in chronic hypertension.

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Available from: Jordan Miller, Sep 03, 2014
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    • "The age-related mechanisms responsible for increased susceptibility of the cerebral circulation to hypertension-induced rupture are likely multifaceted. Previous studies suggest a central role for oxidative stress and redox-sensitive activation of MMPs in the pathogenesis of CMHs, which are known to degrade components of the basal lamina and extracellular matrix, weakening the vascular wall (Wakisaka et al., 2008, 2010a). Although age-related exacerbation of hypertension-induced cerebrovascular ROS production (Fig. 3) and MMP activation (Fig. 4) likely importantly contributed to the increased fragility of aged cerebral arteries, further studies are evidently needed to establish a direct causal link between MMP activation and the development of CMHs in the aged brain. "
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