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
Source: PubMed


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.

Download full-text


Available from: Jordan Miller, Sep 03, 2014
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent studies demonstrate that aging exacerbates hypertension-induced cognitive decline, but the specific age-related mechanisms remain elusive. Cerebral microhemorrhages (CMHs) are associated with rupture of small intracerebral vessels and are thought to progressively impair neuronal function. To determine whether aging exacerbates hypertension-induced CMHs young (3 months) and aged (24 months) mice were treated with angiotensin II plus L-NAME. We found that the same level of hypertension leads to significantly earlier onset and increased incidence of CMHs in aged mice than in young mice, as shown by neurological examination, gait analysis, and histological assessment of CMHs in serial brain sections. Hypertension-induced cerebrovascular oxidative stress and redox-sensitive activation of matrix metalloproteinases (MMPs) were increased in aging. Treatment of aged mice with resveratrol significantly attenuated hypertension-induced oxidative stress, inhibited vascular MMP activation, significantly delayed the onset, and reduced the incidence of CMHs. Collectively, aging promotes CMHs in mice likely by exacerbating hypertension-induced oxidative stress and MMP activation. Therapeutic strategies that reduce microvascular oxidative stress and MMP activation may be useful for the prevention of CMHs, protecting neurocognitive function in high-risk elderly patients.
    Full-text · Article · Feb 2015 · Aging cell
  • Source
    • "Previous studies from our group have demonstrated that oxidative stress caused by mercury exposure decreases the bioavailability of nitric oxide (NO) and alters the expression of NO synthase (NOS), leading to increased vasoconstriction, the reduction of endothelial vasodilator response and the stimulation of cyclooxygenase (COX)-derived vasoconstrictor prostanoids release [11]–[14]. NADPH oxidase, a multisubunit enzymatic complex, has been considered the major source of ROS in vascular cells [15] and has been suggested to be responsible for the endothelial dysfunction observed in different cardiovascular pathologies [10], [16]. Interestingly, previous studies have also reported that the activation of NADPH oxidase may be associated with exposure to mercury in mesenteric and coronary arteries [12], [14]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Unlabelled: Mercury increases the risk of cardiovascular disease and oxidative stress and alters vascular reactivity. This metal elicits endothelial dysfunction causing decreased NO bioavailability via increased oxidative stress and contractile prostanoid production. NADPH oxidase is the major source of reactive oxygen species (ROS) in the vasculature. Our aim was to investigate whether treatment with apocynin, an NADPH oxidase inhibitor, prevents the vascular effects caused by chronic intoxication with low concentrations of mercury. Three-month-old male Wistar rats were treated for 30 days with a) intramuscular injections (i.m.) of saline; b) HgCl(2) (i.m. 1(st) dose: 4.6 µg/kg, subsequent doses: 0.07 µg/kg/day); c) Apocynin (1.5 mM in drinking water plus saline i.m.); and d) Apocynin plus HgCl(2). The mercury treatment resulted in 1) an increased aortic vasoconstrictor response to phenylephrine and reduced endothelium-dependent responses to acetylcholine; 2) the increased involvement of ROS and vasoconstrictor prostanoids in response to phenylephrine, whereas the endothelial NO modulation of such responses was reduced; and 3) the reduced activity of aortic superoxide dismutase (SOD) and glutathione peroxidase (GPx) and increased plasma malondialdehyde (MDA) levels. Treatment with apocynin partially prevented the increased phenylephrine responses and reduced the endothelial dysfunction elicited by mercury treatment. In addition, apocynin treatment increased the NO modulation of vasoconstrictor responses and aortic SOD activity and reduced plasma MDA levels without affecting the increased participation of vasoconstrictor prostanoids observed in aortic segments from mercury-treated rats. Conclusions: Mercury increases the vasoconstrictor response to phenylephrine by reducing NO bioavailability and increasing the involvement of ROS and constrictor prostanoids. Apocynin protects the vessel from the deleterious effects caused by NADPH oxidase, but not from those caused by prostanoids, thus demonstrating a two-way action.
    Full-text · Article · Feb 2013 · PLoS ONE
  • Source
    • "The first experimental model of spontaneous intracerebral hemorrhage in hypertensive mice utilized double transgenic mice with overexpression of human rennin and human angiotensinogen, treated with No-nitro-l-arginine methyl ester (l-NAME), an inhibitor of nitric oxide synthase, and high-salt diet [83, 84]. But because this model requires crossing the two transgenic mouse lines, it is not easily applied to other transgenic mouse models, such as many APP transgenic mouse models. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Stroke prevention efforts typically focus on either ischemic or hemorrhagic stroke. This approach is overly simplistic due to the frequent coexistence of ischemic and hemorrhagic cerebrovascular disease. This coexistence, termed "mixed cerebrovascular disease", offers a conceptual framework that appears useful for stroke prevention strategies. Mixed cerebrovascular disease incorporates clinical and subclinical syndromes, including ischemic stroke, subclinical infarct, white matter disease of aging (leukoaraiosis), intracerebral hemorrhage, and cerebral microbleeds. Reliance on mixed cerebrovascular disease as a diagnostic entity may assist in stratifying risk of hemorrhagic stroke associated with platelet therapy and anticoagulants. Animal models of hemorrhagic cerebrovascular disease, particularly models of cerebral amyloid angiopathy and hypertension, offer novel means for identifying underlying mechanisms and developing focused therapy. Phosphodiesterase (PDE) inhibitors represent a class of agents that, by targeting both platelets and vessel wall, provide the kind of dual actions necessary for stroke prevention, given the spectrum of disorders that characterizes mixed cerebrovascular disease.
    Full-text · Article · Jul 2012 · Translational Stroke Research
Show more