Abstract 38: Reactive Oxygen Species Contribute To Aneurysmal Rupture in Mice

Background and Purpose: Inflammation and apoptosis are recognized as key factors for aneurysmal rupture. Reactive oxygen species (ROS) mediates both inflammation and apoptosis in vascular walls. Therefore, we hypothesized that ROS produced by xanthine oxidase and NADPH oxidase contributes to aneurysmal rupture. Recently we have demonstrated the feasibility of using a mouse model of intracranial aneurysms to test pharmacological therapies for the prevention of aneurysmal rupture. We tested the hypothesis by using this newly established mouse model. Methods: Intracranial aneurysms were induced in male mice using a combination of a single injection of elastase into the cerebrospinal fluid and the deoxycorticosterone acetate (DOCA) salt hypertension. Six days after aneurysm induction, we started 2-week treatment with vehicle (n=27), a superoxide scavenger (tempol; n=13), a xanthine oxidase inhibitor (oxypurinol; n=15), and a NADPH oxidase inhibitor (apocynin; n=16). Aneurysmal rupture was detected by neurological symptoms and confirmed by the presence of intracranial aneurysms with subarachnoid hemorrhage. Dihydroethidium staining and in situ zymography were performed to detect superoxide production and gelatinase activity, respectively. Results: A superoxide scavenger (tempol) significantly reduced rupture rate (vehicle vs. tempol: 74% vs. 27%, P < 0.05) (Figure1). It reduced superoxide production and gelatinase activity in aneurysmal walls (Figure2). Furthermore, the xanthine oxidase inhibitor (oxypurinol), and the NADPH oxidase inhibitor (apocynin) reduced the rupture rate (vehicle vs. oxypurinol: 74% vs. 30%, P< 0.05, vehicle vs. apocynin: 74% vs. 33%, P < 0.05). Conclusion: Our results indicate that superoxide produced by xanthine oxidase and NADPH oxidase contributes to aneurysmal rupture, by activating matrix metalloproteinases.

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Pterin-6-aldehyde, Xanthine Oxidase Inhibitor and Superoxide Scavenger, Directly React with Peroxynitrite

Pteridines ◽

10.1515/pteridines.1999.10.1.32 ◽

1999 ◽

Vol 10 (1) ◽

pp. 32-34

Author(s):

Hiroko Mori ◽

Toshiyuki Arai ◽

Hisanari Ishii ◽

Nobuyuki Endo ◽

Toshinori Suzuki ◽

...

Keyword(s):

Uric Acid ◽

Xanthine Oxidase ◽

High Performance ◽

Reversed Phase ◽

Oxidase Inhibitor ◽

Tyrosine Nitration ◽

Oxygen Species ◽

Xanthine Oxidase Inhibitor ◽

Rp Hplc ◽

Superoxide Scavenger

The effect of pterin-6-aldehyde (P6A), xanthine oxidase inhibitor and superoxide scavenger, on the production of nitrotyrosine as a footprint of tyrosine nitration by peroxynitrite, was compared with that of uric acid, a peroxynitrite scavenger. The amounts of tyrosine, P6A and nitrotyrosine were quantified using reversed-phase high-performance liquid chromato-graphy (RP-HPLC). P6A suppressed nitrotyrosine formation less effectively than uric acid, that is, 0.25 mM P6A reduced nitrotyrosine formation to 67.9± 10.8%, while 0.025 mM uric acid reduced it to 34.2± 1.6%. In living systems, peroxynitrite is generated by the reaction of super-oxide with nitric oxide and has a variety of toxic effects. Our results show that P6A is not necessarily a strong scavenger of peroxynitrite. However, since P6A is a potent scavenger of superoxide, P6A is thought to totally suppress peroxynitrite generation. Compounds that scavenge both superoxide and peroxynitrite may be useful in tissue damage in which reactive oxygen species are involved.

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Effects of 6-formylpterin, a xanthine oxidase inhibitor and a superoxide scavenger, on production of nitric oxide in RAW 264.7 macrophages

Biochimica et Biophysica Acta (BBA) - General Subjects ◽

10.1016/s0304-4165(99)00210-x ◽

2000 ◽

Vol 1474 (1) ◽

pp. 93-99 ◽

Cited By ~ 7

Author(s):

H Mori

Keyword(s):

Nitric Oxide ◽

Xanthine Oxidase ◽

Oxidase Inhibitor ◽

Raw 264.7 ◽

Xanthine Oxidase Inhibitor ◽

Raw 264.7 Macrophages ◽

Superoxide Scavenger

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Oxypurinol, a xanthine oxidase inhibitor and a superoxide scavenger, did not attenuate ischemic neuronal damage in gerbils

Life Sciences ◽

10.1016/s0024-3205(98)00312-9 ◽

1998 ◽

Vol 63 (7) ◽

pp. PL107-PL112 ◽

Cited By ~ 5

Author(s):

Toshiyuki Arai ◽

Hiroko Mori ◽

Hisanari Ishii ◽

Takehiko Adachi ◽

Nobuyuki Endo ◽

...

Keyword(s):

Xanthine Oxidase ◽

Neuronal Damage ◽

Oxidase Inhibitor ◽

Xanthine Oxidase Inhibitor ◽

Superoxide Scavenger

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Reduction in Impulse Noise-Induced Permanent Threshold Shift with Intracochlear Application of an NADPH Oxidase Inhibitor

Journal of the American Academy of Audiology ◽

10.3766/jaaa.24.6.3 ◽

2013 ◽

Vol 24 (06) ◽

pp. 461-473 ◽

Cited By ~ 18

Author(s):

Eric C. Bielefeld

Keyword(s):

Reactive Oxygen Species ◽

Nadph Oxidase ◽

Impulse Noise ◽

Noise Exposure ◽

Oxidase Inhibitor ◽

Threshold Shift ◽

Distilled Water ◽

Oxygen Species ◽

Nadph Oxidase Inhibitor ◽

Continuous Noise

Background: Toxic levels of reactive oxygen species are key contributors to the lesion of dead outer hair cells (OHCs) seen in the cochlea after noise exposure. The current study follows previous work in which paraquat was used to demonstrate that NADPH oxidase is active in the cochlea and can contribute to cochlear reactive oxygen species formation and hair cell loss. Purpose: The current study was undertaken to test whether pharmacological blockade of NADPH oxidase in the cochlea would lead to reduced noise-induced hearing loss and OHC death. Study Sample: A total of 18 chinchillas (36 ears) were assessed in the study. Intervention: AEBSF (4-[2-aminoethyl]benzenesulfonyl fluoride), an inhibitor of NADPH oxidase activation, was dissolved in distilled water and delivered into the cochlea via diffusion across the round window membrane. The contralateral ears received distilled water as a vehicle control. Following treatment, chinchillas were exposed to one of two noises: a 4 kHz octave band noise at 106 dB SPL for 6 hr or an impulse noise that consisted of 75 pairs of 155 dB pSPL impulses. Data Collection and Analysis: Pre– and post–noise exposure, thresholds of the auditory brainstem response at 2–8 kHz were measured. Postmortem OHC counts were conducted at the conclusion of the study. Two- and three-factor ANOVAs were used for statistical analysis of the OHC losses and ABR threshold shifts induced by the noise exposures. Results: Permanent threshold shift from the impulse noise was reduced in the ears treated with the NADPH oxidase inhibitor, but no differences were found in the groups exposed to the continuous noise. OHC losses were not statistically different between the treated and untreated ears for either noise exposure. Conclusions: The results suggest that NADPH oxidase-mediated superoxide has a role in cochlear damage from impulse noise, and pharmacologic inhibition of NADPH oxidase can reduce cochlear susceptibility to noise damage. The lack of protection from the longer-duration continuous noise can be attributed to a number of possibilities related to dose level and delivery schedule.

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6-formylpterin, a xanthine oxidase inhibitor, intracellularly generates reactive oxygen species involved in apoptosis and cell proliferation

Free Radical Biology and Medicine ◽

10.1016/s0891-5849(00)00465-2 ◽

2001 ◽

Vol 30 (3) ◽

pp. 248-259 ◽

Cited By ~ 19

Author(s):

Toshiyuki Arai ◽

Nobuyuki Endo ◽

Kouhei Yamashita ◽

Masataka Sasada ◽

Hiroko Mori ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Cell Proliferation ◽

Xanthine Oxidase ◽

Reactive Oxygen ◽

Oxidase Inhibitor ◽

Oxygen Species ◽

Xanthine Oxidase Inhibitor

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Thyroid Hormone-Induced Cytosol-to-Nuclear Translocation of Rat Liver Nrf2 Is Dependent on Kupffer Cell Functioning

The Scientific World JOURNAL ◽

10.1100/2012/301494 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Luis A. Videla ◽

Pamela Cornejo ◽

Pamela Romanque ◽

Catherine Santibáñez ◽

Iván Castillo ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Nadph Oxidase ◽

Kupffer Cell ◽

Respiratory Burst ◽

Oxidase Inhibitor ◽

Burst Activity ◽

Oxygen Species ◽

Respiratory Burst Activity ◽

Nadph Oxidase Inhibitor ◽

Nrf2 Activation

L-3,3′,5-triiodothyronine (T3) administration upregulates nuclear factor-E2-related factor 2 (Nrf2) in rat liver, which is redox-sensitive transcription factor mediating cytoprotection. In this work, we studied the role of Kupffer cell respiratory burst activity, a process related to reactive oxygen species generation and liver homeostasis, in Nrf2 activation using the macrophage inactivator gadolinium chloride (GdCl3; 10 mg/kg i.v. 72 h before T3[0.1 mg/kg i.p.]) or NADPH oxidase inhibitor apocynin (1.5 mmol/L added to the drinking water for 7 days before T3), and determinations were performed 2 h after T3. T3increased nuclear/cytosolic Nrf2 content ratio and levels of heme oxygenase 1 (HO-1), catalytic subunit of glutamate cysteine ligase, and thioredoxin (Western blot) over control values, proteins whose gene transcription is induced by Nrf2. These changes were suppressed by GdCl3treatment prior to T3, an agent-eliciting Kupffer-cell depletion, inhibition of colloidal carbon phagocytosis, and the associated respiratory burst activity, with enhancement in nuclear inhibitor of Nrf2 kelch-like ECH-associated protein 1 (Keap1)/Nrf2 content ratios suggesting Nrf2 degradation. Under these conditions, T3-induced tumor necrosis factor-α(TNF-α) response was eliminated by previous GdCl3administration. Similar to GdCl3, apocynin given before T3significantly reduced liver Nrf2 activation and HO-1 expression, a NADPH oxidase inhibitor eliciting abolishment of colloidal carbon-induced respiratory burst activity without altering carbon phagocytosis. It is concluded that Kupffer cell functioning is essential for upregulation of liver Nrf2-signaling pathway by T3. This contention is supported by suppression of the respiratory burst activity of Kupffer cells and the associated reactive oxygen species production by GdCl3or apocynin given prior to T3, thus hindering Nrf2 activation.

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Antioxidant pyruvate inhibits cardiac formation of reactive oxygen species through changes in redox state

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.279.5.h2431 ◽

2000 ◽

Vol 279 (5) ◽

pp. H2431-H2438 ◽

Cited By ~ 90

Author(s):

Eberhard Bassenge ◽

Olaf Sommer ◽

Michael Schwemmer ◽

Rolf Bünger

Keyword(s):

Reactive Oxygen Species ◽

Xanthine Oxidase ◽

Nadh Oxidase ◽

Ischemia Reperfusion ◽

Reactive Oxygen ◽

Oxidase Inhibitor ◽

Oxygen Species ◽

Xanthine Oxidase Inhibitor ◽

Ros Formation ◽

Myocardial Ischemia Reperfusion

Myocardial ischemia-reperfusion is associated with bursts of reactive oxygen species (ROS) such as superoxide radicals (O2 −·). Membrane-associated NADH oxidase (NADHox) activity is a hypothetical source of O2 −·, implying the NADH concentration-to-NAD+ concentration ratio ([NADH]/[NAD+]) as a determinant of ROS. To test this hypothesis, cardiac NADHox and ROS formation were measured as influenced by pyruvate or l-lactate. Pre- and postischemic Langendorff guinea pig hearts were perfused at different pyruvate/l-lactate concentrations to alter cytosolic [NADH]/[NAD+]. NADHox and ROS were measured with the use of lucigenin chemiluminescence and electron spin resonance, respectively. In myocardial homogenates, pyruvate (0.05, 0.5 mM) and the NADHox blocker hydralazine markedly inhibited NADHox (16 ± 2%, 58 ± 9%). In postischemic hearts, pyruvate (0.1–5.0 mM) dose dependently inhibited ROS up to 80%. However,l-lactate (1.0–15.0 mM) stimulated both basal and postischemic ROS severalfold. Furthermore,l-lactate-induced basal ROS was dose dependently inhibited by pyruvate (0.1–5.0 mM) and not the xanthine oxidase inhibitor oxypurinol. Pyruvate did not inhibit ROS from xanthine oxidase. The data suggest a substantial influence of cytosolic NADH on cardiac O2 −· formation that can be inhibited by submillimolar pyruvate. Thus cytotoxicities due to cardiac ischemia-reperfusion ROS may be alleviated by redox reactants such as pyruvate.

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Vascular Lipotoxicity: Endothelial Dysfunction via Fatty-Acid-Induced Reactive Oxygen Species Overproduction in Obese Zucker Diabetic Fatty Rats

Endocrinology ◽

10.1210/en.2006-1132 ◽

2007 ◽

Vol 148 (1) ◽

pp. 160-165 ◽

Cited By ~ 116

Author(s):

Ichiro Chinen ◽

Michio Shimabukuro ◽

Ken Yamakawa ◽

Namio Higa ◽

Toshihiro Matsuzaki ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Endothelial Dysfunction ◽

Nadph Oxidase ◽

Reactive Oxygen ◽

Oxidase Inhibitor ◽

Ros Production ◽

Oxygen Species ◽

Oxidase Subunit ◽

Nadph Oxidase Inhibitor ◽

Zdf Rats

Vascular endothelial dysfunction has been demonstrated in obesity, but the molecular basis for this link has not been clarified. We examined the role of free fatty acids (FFA) on vascular reactivity in the obese fa/fa Zucker diabetic fatty (ZDF) rat. Addition of acetylcholine produced a dose-dependent relaxation in aortic rings of ZDF and lean +/+ rats, but the ED50 value was higher in ZDF (−6.80 ± 0.05 vs. −7.11 ± 0.05 log10 mol/liter, P = 0.033). A 2-wk treatment with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, pitavastatin (3 mg/kg/d) or a reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin (5 mmol/liter in drinking water), improved the response in ZDF (ED50, −7.16 ± 0.03 and −7.14 ± 0.05 log10 mol/liter, P = 0.008 and P = 0.015 vs. vehicle, respectively). Vasodilator response to sodium nitroprusside was identical between ZDF and +/+ rats. Vascular reactive oxygen species (ROS) levels and NADPH oxidase activity in aorta were increased in ZDF rats but were decreased by pitavastatin. In in vitro cell culture, intracellular ROS signal and NADPH oxidase subunit mRNA were increased by palmitate, but this palmitate-induced ROS production was inhibited by NADPH oxidase inhibitor or pitavastatin. In conclusion, FFA-induced NADPH oxidase subunit overexpression and ROS production could be involved in the endothelial dysfunction seen in obese ZDF rats, and this could be protected by pitavastatin or NADPH oxidase inhibitors.

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