Extracellular Superoxide Dismutase

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Tim D Oury - One of the best experts on this subject based on the ideXlab platform.

  • Extracellular Superoxide Dismutase protects against proteinuric kidney disease
    Journal of The American Society of Nephrology, 2015
    Co-Authors: Roderick J. Tan, Tim D Oury, Dong Zhou, Liangxiang Xiao, Lili Zhou, Sheldon I Bastacky, Youhua Liu
    Abstract:

    Extracellular Superoxide Dismutase (EC-SOD), also known as SOD3, is an antioxidant expressed at high levels in normal adult kidneys. Because oxidative stress contributes to a variety of kidney injuries, we hypothesized that EC-SOD may be protective in CKD progression. To study this hypothesis, we used a murine model of ADR nephropathy characterized by albuminuria and renal dysfunction. We found that levels of EC-SOD diminished throughout the course of disease progression and were associated with increased levels of NADPH oxidase and oxidative stress markers. EC-SOD null mice were sensitized to ADR injury, as evidenced by increases in albuminuria, serum creatinine, histologic damage, and oxidative stress. The absence of EC-SOD led to increased levels of NADPH oxidase and an increase in β-catenin signaling, which has been shown to be pathologic in a variety of kidney injuries. Exposure of EC-SOD null mice to either chronic angiotensin II infusion or to daily albumin injections also caused increased proteinuria. In contrast, EC-SOD null mice subjected to nonproteinuric CKD induced by unilateral ureteral obstruction exhibited no differences compared with wild-type mice. Finally, we also found a decrease in EC-SOD in human CKD biopsy samples, similar to our findings in mice. Therefore, we conclude that EC-SOD is protective in CKDs characterized by proteinuria.

  • Extracellular Superoxide Dismutase regulates cardiac function and fibrosis.
    Journal of Molecular and Cellular Cardiology, 2009
    Co-Authors: Corrine R. Kliment, Hagir B. Suliman, Jacob M. Tobolewski, Crystal M. Reynolds, Kenneth R. Mcgaffin, Claude A. Piantadosi, Charles F. Mctiernan, Tim D Oury
    Abstract:

    Abstract Extracellular Superoxide Dismutase (EC-SOD) is an antioxidant that protects the heart from ischemia and the lung from inflammation and fibrosis. The role of cardiac EC-SOD under normal conditions and injury remains unclear. Cardiac toxicity, a common side effect of doxorubicin, involves oxidative stress. We hypothesize that EC-SOD is critical for normal cardiac function and protects the heart from oxidant-induced fibrosis and loss of function. C57BL/6 and EC-SOD-null mice were treated with doxorubicin, 15 mg/kg (i.p.). After 15 days, echocardiography was used to assess cardiac function. Left ventricle (LV) tissue was used to assess fibrosis and inflammation by staining, Western blot, and hydroxyproline analysis. At baseline, EC-SOD-null mice have LV wall thinning and increases in LV end diastolic dimensions compared to wild-type mice but have normal cardiac function. After doxorubicin, EC-SOD-null mice have decreases in fractional shortening not apparent in WT mice. Lack of EC-SOD also leads to increases in myocardial apoptosis and significantly more LV fibrosis and inflammatory cell infiltration. Administration of the metalloporphyrin AEOL 10150 abrogates the loss of cardiac function, and potentially fibrosis, associated with doxorubicin treatment in both wild-type and EC-SOD KO mice. EC-SOD is critical for normal cardiac morphology and protects the heart from oxidant-induced fibrosis, apoptosis, and loss of function. The antioxidant metalloporphyrin AEOL 10150 effectively protects cardiac function from doxorubicin-induced oxidative stress in vivo. These findings identify targets for the use of antioxidant agents in oxidant-induced cardiac fibrosis.

  • Extracellular Superoxide Dismutase protects the heart against oxidative stress and hypertrophy after myocardial infarction
    Free Radical Biology and Medicine, 2008
    Co-Authors: Elza D Van Deel, Tim D Oury, Robert J Bache, Guangshuo Zhu, Dirk J Duncker, Yingjie Chen
    Abstract:

    Extracellular Superoxide Dismutase (EC-SOD) contributes only a small fraction to total SOD activity in the heart but is strategically located to scavenge free radicals in the Extracellular compartment. EC-SOD expression is decreased in myocardial-infarction (MI)-induced heart failure, but whether EC-SOD can abrogate oxidative stress or modify MI-induced ventricular remodeling has not been previously studied. Consequently, the effects of EC-SOD gene deficiency (EC-SOD KO) on left ventricular (LV) oxidative stress, hypertrophy, and fibrosis were studied in EC-SOD KO and wild-type mice under control conditions, and at 4 and 8 weeks after permanent coronary artery ligation. EC-SOD KO had no detectable effect on LV function in normal hearts but caused small but significant increases of LV fibrosis. At 8 weeks after MI, EC-SOD KO mice developed significantly more LV hypertrophy (LV mass increased 1.64-fold in KO mice compared to 1.35-fold in wild-type mice; p<0.01) and more fibrosis and myocyte hypertrophy which was more prominent in the peri-infarct region than in the remote myocardium. EC-SOD KO mice had greater increases of nitrotyrosine in the peri-infarct myocardium, and this was associated with a greater reduction of LV ejection fraction, a greater decrease of sarcoplasmic or endoplasmic reticulum calcium2+ ATPase, and a greater increase of atrial natriuretic peptide in the peri-infarct zone compared to wild-type mice. EC-SOD KO was associated with more increases of phosphorylated p38 (p-p38(Thr180/Tyr182)), p42/44 Extracellular signal-regulated kinase (p-Erk(Thr202/Tyr204)), and c-Jun N-terminal kinase (p-JNK(Thr183/Tyr185)) both under control conditions and after MI, indicating that EC-SOD KO increases activation of mitogen-activated protein kinase signaling pathways. These findings demonstrate that EC-SOD plays an important role in protecting the heart against oxidative stress and infarction-induced ventricular hypertrophy.

  • Extracellular Superoxide Dismutase inhibits inflammation by preventing oxidative fragmentation of hyaluronan
    Journal of Biological Chemistry, 2008
    Co-Authors: Fei Gao, Jacob M. Tobolewski, Jeffrey R Koenitzer, Dianhua Jiang, Jiurong Liang, Paul W Noble, Tim D Oury
    Abstract:

    Extracellular Superoxide Dismutase (EC-SOD) is expressed at high levels in lungs. EC-SOD has a polycationic matrix-binding domain that binds to polyanionic constituents in the matrix. Previous studies indicate that EC-SOD protects the lung in both bleomycin- and asbestos-induced models of pulmonary fibrosis. Although the mechanism of EC-SOD protection is not fully understood, these studies indicate that EC-SOD plays an important role in regulating inflammatory responses to pulmonary injury. Hyaluronan is a polyanionic high molecular mass polysaccharide found in the Extracellular matrix that is sensitive to oxidant-mediated fragmentation. Recent studies found that elevated levels of low molecular mass hyaluronan are associated with inflammatory conditions. We hypothesize that EC-SOD may inhibit pulmonary inflammation in part by preventing Superoxide-mediated fragmentation of hyaluronan to low molecular mass fragments. We found that EC-SOD directly binds to hyaluronan and significantly inhibits oxidant-induced degradation of this glycosaminoglycan. In vitro human polymorphic neutrophil chemotaxis studies indicate that oxidative fragmentation of hyaluronan results in polymorphic neutrophil chemotaxis and that EC-SOD can completely prevent this response. Intratracheal injection of crocidolite asbestos in mice leads to pulmonary inflammation and injury that is enhanced in EC-SOD knock-out mice. Notably, hyaluronan levels are increased in the bronchoalveolar lavage fluid after asbestos-induced pulmonary injury, and this response is markedly enhanced in EC-SOD knock-out mice. These data indicate that inhibition of oxidative hyaluronan fragmentation probably represents one mechanism by which EC-SOD inhibits inflammation in response to lung injury.

  • Extracellular Superoxide Dismutase protects against matrix degradation of heparan sulfate in the lung
    Antioxidants & Redox Signaling, 2008
    Co-Authors: Corrine R. Kliment, Jacob M. Tobolewski, Jan J Enghild, Roderick J. Tan, Michelle L Manni, Tim D Oury
    Abstract:

    Asbestosis is a form of interstitial lung disease caused by the inhalation of asbestos fibers, leading to inflammation and pulmonary fibrosis. Inflammation and oxidant/antioxidant imbalances are known to contribute to the disease pathogenesis. Extracellular Superoxide Dismutase (EC-SOD) is an antioxidant enzyme that has been shown to protect the lung from oxidant-mediated damage, inflammation, and interstitial fibrosis. Extracellular matrix (ECM) components, such as collagen and glycosaminoglycans, are known to be sensitive to oxidative fragmentation. Heparan sulfate, a glycosaminoglycan, is highly abundant in the ECM and tightly binds EC-SOD. We investigated the protective role of EC-SOD by evaluating the interaction of EC-SOD with heparan sulfate in the presence of reactive oxygen species (ROS). We found that ROS-induced heparin and heparan sulfate fragments induced neutrophil chemotaxis across a modified Boyden chamber, which was inhibited by the presence of EC-SOD by scavenging oxygen radicals. Chemotaxis in response to oxidatively fragmented heparin was mediated by Toll-like receptor-4. In vivo, bronchoalveolar lavage fluid from EC-SOD knockout mice at 1, 14, and 28 days after asbestos exposure showed increased heparan sulfate shedding from the lung parenchyma. We demonstrate that one mechanism through which EC-SOD inhibits lung inflammation and fibrosis in asbestosis is by protecting heparin/heparan sulfate from oxidative fragmentation.

James D Crapo - One of the best experts on this subject based on the ideXlab platform.

  • Extracellular Superoxide Dismutase in macrophages augments bacterial killing by promoting phagocytosis
    American Journal of Pathology, 2011
    Co-Authors: Michelle L Manni, James D Crapo, Lauren Tomai, Callie A Norris, Michael L Thomas, Eric E Kelley, Russell D Salter, Lingyi L Chang, Simon C Watkins, Jon D Piganelli
    Abstract:

    Extracellular Superoxide Dismutase (EC-SOD) is abundant in the lung and limits inflammation and injury in response to many pulmonary insults. To test the hypothesis that EC-SOD has an important role in bacterial infections, wild-type and EC-SOD knockout (KO) mice were infected with Escherichia coli to induce pneumonia. Although mice in the EC-SOD KO group demonstrated greater pulmonary inflammation than did wild-type mice, there was less clearance of bacteria from their lungs after infection. Macrophages and neutrophils express EC-SOD; however, its function and subcellular localization in these inflammatory cells is unclear. In the present study, immunogold electron microscopy revealed EC-SOD in membrane-bound vesicles of phagocytes. These findings suggest that inflammatory cell EC-SOD may have a role in antibacterial defense. To test this hypothesis, phagocytes from wild-type and EC-SOD KO mice were evaluated. Although macrophages lacking EC-SOD produced more reactive oxygen species than did cells expressing EC-SOD after stimulation, they demonstrated significantly impaired phagocytosis and killing of bacteria. Overall, this suggests that EC-SOD facilitates clearance of bacteria and limits inflammation in response to infection by promoting bacterial phagocytosis.

  • Extracellular Superoxide Dismutase protects against pulmonary emphysema by attenuating oxidative fragmentation of ecm
    Proceedings of the National Academy of Sciences of the United States of America, 2010
    Co-Authors: Hongwei Yao, Vuokko L. Kinnula, James D Crapo, Gnanapragasam Arunachalam, Jaewoong Hwang, Sangwoon Chung, Isaac K Sundar, Irfan Rahman
    Abstract:

    Extracellular Superoxide Dismutase (ECSOD or SOD3) is highly expressed in lungs and functions as a scavenger of O2• ─. ECM fragmentation, which can be triggered by oxidative stress, participates in the pathogenesis of chronic obstructive pulmonary disease (COPD) through attracting inflammatory cells into the lungs. The level of SOD3 is significantly decreased in lungs of patients with COPD. However, the role of endogenous SOD3 in the development/progression of emphysema is unknown. We hypothesized that SOD3 protects against emphysema by attenuating oxidative fragmentation of ECM in mice. To test this hypothesis, SOD3-deficient, SOD3-transgenic, and WT C57BL/6J mice were exposed to cigarette smoke (CS) for 3 d (300 mg total particulate matter/m3) to 6 mo (100 mg/m3 total particulate matter) or by intratracheal elastase injection. Airspace enlargement, lung inflammation, lung mechanical properties, and exercise tolerance were determined at different time points during CS exposure or after elastase administration. CS exposure and elastase administration caused airspace enlargement as well as impaired lung function and exercise capacity in SOD3-null mice, which were improved in mice overexpressing SOD3 and by pharmacological SOD mimetic. These phenomena were associated with SOD3-mediated protection against oxidative fragmentation of ECM, such as heparin sulfate and elastin, thereby attenuating lung inflammatory response. In conclusion, SOD3 attenuates emphysema and reduces oxidative fragmentation of ECM in mouse lung. Thus, pharmacological augmentation of SOD3 in the lung may have a therapeutic potential in the intervention of COPD/emphysema.

  • decreased pulmonary Extracellular Superoxide Dismutase during systemic inflammation
    Free Radical Biology and Medicine, 2008
    Co-Authors: Junji Ueda, James D Crapo, Lingyi Chang, Marlene E Starr, Hitoshi Takahashi, Mark B Evers, Hiroshi Saito
    Abstract:

    Abstract Oxidative damage is a major cause of lung injury during systemic inflammatory response syndrome. In this study, the expression of an antioxidant enzyme, Extracellular Superoxide Dismutase (EC-SOD), and its protective role against pulmonary oxidative damage were investigated using mouse models of systemic inflammation. Intraperitoneal injection with bacterial endotoxin lipopolysaccharides (LPS; 20 mg/kg) caused oxidative damage in lungs as assessed by increased tyrosine nitration in proteins. LPS administration also resulted in a rapid and significant loss of more than 80% of pulmonary EC-SOD in a time- and dose-dependent manner, but other types of SODs, cytoplasmic CuZn-SOD and mitochondrial Mn-SOD, were not affected. EC-SOD protein is most abundant in lungs but also present at high levels in other tissues such as heart and white fat; however, the LPS-mediated decrease in this enzyme was most apparent in the lungs. Intravenous injection of mice with tumor necrosis factor α (10 μg per mouse) also caused a 60% decrease in EC-SOD in the lungs, suggesting that the EC-SOD down-regulation is mediated by this LPS-inducible inflammatory cytokine. A protective role for EC-SOD against LPS-mediated systemic inflammation was shown by an increased survival rate (75% vs 29% in 5 days) and decreased pulmonary oxidative damage in EC-SOD transgenic mice that overexpress the human EC-SOD gene. These results demonstrate that the inflammation-mediated EC-SOD down-regulation has a major pathophysiological impact during the systemic inflammatory response syndrome.

  • Extracellular Superoxide Dismutase and oxidant damage in osteoarthritis
    Arthritis & Rheumatism, 2005
    Co-Authors: Elizabeth A Regan, Russell P Bowler, Karen Tran, Joanne Flannelly, Michael Nicks, Beth Duda Carbone, Deborah H Glueck, Harry F G Heijnen, Roger M Mason, James D Crapo
    Abstract:

    Objective To use human cartilage samples and a mouse model of osteoarthritis (OA) to determine whether Extracellular Superoxide Dismutase (EC-SOD) is a constituent of cartilage and to evaluate whether there is a relationship between EC-SOD deficiency and OA. Methods Samples of human cartilage were obtained from femoral heads at the time of joint replacement surgery for OA or femoral neck fracture. Samples of mouse tibial cartilage obtained from STR/ort mice and CBA control mice were compared at 5, 15, and 35 weeks of age. EC-SOD was measured by enzyme-linked immunosorbent assay, Western blotting, and immunohistochemistry techniques. Real-time quantitative reverse transcription–polymerase chain reaction was used to measure messenger RNA for EC-SOD and for endothelial cell, neuronal, and inducible nitric oxide synthases. Nitrotyrosine formation was assayed by Western blotting in mouse cartilage and by fluorescence immunohistochemistry in human cartilage. Results Human articular cartilage contained large amounts of EC-SOD (mean ± SEM 18.8 ± 3.8 ng/gm wet weight of cartilage). Cartilage from patients with OA had an ∼4-fold lower level of EC-SOD compared with cartilage from patients with hip fracture. Young STR/ort mice had decreased levels of EC-SOD in tibial cartilage before histologic evidence of disease occurred, as well as significantly more nitrotyrosine formation at all ages studied. Conclusion EC-SOD, the major scavenger of reactive oxygen species in Extracellular spaces, is decreased in humans with OA and in an animal model of OA. Our findings suggest that inadequate control of reactive oxygen species plays a role in the pathophysiology of OA.

  • Extracellular Superoxide Dismutase ec sod binds to type i collagen and protects against oxidative fragmentation
    Journal of Biological Chemistry, 2004
    Co-Authors: Steen V Petersen, Cheryl L. Fattman, Tim D Oury, Russell P Bowler, Ida B Thogersen, Zuzana Valnickova, Louise Ostergaard, Joanna Wegrzyn, Christian Jacobsen, James D Crapo
    Abstract:

    The antioxidant enzyme Extracellular Superoxide Dismutase (EC-SOD) is mainly found in the Extracellular matrix of tissues. EC-SOD participates in the detoxification of reactive oxygen species by catalyzing the dismutation of Superoxide radicals. The tissue distribution of the enzyme is particularly important because of the reactive nature of its substrate, and it is likely essential that EC-SOD is positioned at the site of Superoxide production to prevent adventitious oxidation. EC-SOD contains a C-terminal heparin-binding region thought to be important for modulating its distribution in the Extracellular matrix. This paper demonstrates that, in addition to binding heparin, EC-SOD specifically binds to type I collagen with a dissociation constant (K(d)) of 200 nm. The heparin-binding region was found to mediate the interaction with collagen. Notably, the bound EC-SOD significantly protects type I collagen from oxidative fragmentation. This expands the known repertoire of EC-SOD binding partners and may play an important physiological role in preventing oxidative fragmentation of collagen during oxidative stress.

Tohru Fukai - One of the best experts on this subject based on the ideXlab platform.

  • Role of Copper Transport Protein Antioxidant 1 in Angiotensin II–Induced Hypertension A Key Regulator of Extracellular Superoxide Dismutase
    Hypertension (Dallas Tex. : 1979), 2012
    Co-Authors: Kiyoshi Ozumi, Gin-fu Chen, Ha Won Kim, Ronald D. Mckinney, Lydia Finney, Masuko Ushio-fukai, Varadarajan Sudhahar, Stefan Vogt, Takashi Kohno, Tohru Fukai
    Abstract:

    Extracellular Superoxide Dismutase (SOD3) is a secretory copper enzyme involved in protecting angiotensin II (Ang II)–induced hypertension. We found previously that Ang II upregulates SOD3 expression and activity as a counterregulatory mechanism; however, underlying mechanisms are unclear. Antioxidant 1 (Atox1) is shown to act as a copper-dependent transcription factor, as well as a copper chaperone, for SOD3 in vitro, but its role in Ang II–induced hypertension in vivo is unknown. Here we show that Ang II infusion increases Atox1 expression, as well as SOD3 expression and activity, in aortas of wild-type mice, which are inhibited in mice lacking Atox1. Accordingly, Ang II increases vascular Superoxide production, reduces endothelium-dependent vasodilation, and increases vasoconstriction in mesenteric arteries to a greater extent in Atox1 −/− than in wild-type mice. This contributes to augmented hypertensive response to Ang II in Atox1 −/− mice. In cultured vascular smooth muscle cells, Ang II promotes translocation of Atox1 to the nucleus, thereby increasing SOD3 transcription by binding to Atox1-responsive element in the SOD3 promoter. Furthermore, Ang II increases Atox1 binding to the copper exporter ATP7A, which obtains copper from Atox1, as well as translocation of ATP7A to plasma membranes, where it colocalizes with SOD3. As its consequence, Ang II decreases vascular copper levels, which is inhibited in Atox1 −/− mice. In summary, Atox1 functions to prevent Ang II–induced endothelial dysfunction and hypercontraction in resistant vessels, as well as hypertension, in vivo by reducing Extracellular Superoxide levels via increasing vascular SOD3 expression and activity.

  • hydrogen peroxide regulates Extracellular Superoxide Dismutase activity and expression in neonatal pulmonary hypertension
    Antioxidants & Redox Signaling, 2011
    Co-Authors: Stephen Wedgwood, Tohru Fukai, Satyanarayana Lakshminrusimha, James A Russell, Paul T Schumacker, Robin H Steinhorn
    Abstract:

    Abstract We previously demonstrated that Superoxide and H2O2 promote pulmonary arterial vasoconstriction in a lamb model of persistent pulmonary hypertension of the newborn (PPHN). Because Extracellular Superoxide Dismutase (ecSOD) augments vasodilation, we hypothesized that H2O2-mediated ecSOD inactivation contributes to pulmonary arterial vasoconstriction in PPHN lambs. ecSOD activity was decreased in pulmonary arterial smooth muscle cells (PASMCs) isolated from PPHN lambs relative to controls. Exposure to 95% O2 to mimic hyperoxic ventilation reduced ecSOD activity in control PASMCs. In both cases, these events were associated with increased protein thiol oxidation, as detected by the redox sensor roGFP. Accordingly, exogenous H2O2 decreased ecSOD activity in control PASMCs, and PEG-catalase restored ecSOD activity in PPHN PASMCs. In intact animal studies, ecSOD activity was decreased in fetal PPHN lambs, and in PPHN lambs ventilated with 100% O2 relative to controls. In ventilated PPHN lambs, administ...

  • protective role of Extracellular Superoxide Dismutase in renal ischemia reperfusion injury
    Kidney International, 2010
    Co-Authors: Tohru Fukai, David G. Harrison, Markus P Schneider, Jennifer C Sullivan, Paul F Wach, Erika I Boesen, Tatsuo Yamamoto, David M Pollock, Jennifer S Pollock
    Abstract:

    Extracellular Superoxide Dismutase (SOD3) is highly expressed in renal tissues and a critical regulator of vascular function. We hypothesized that deletion of SOD3 would attenuate recovery of renal blood flow (RBF) and increase oxidative stress and injury following renal ischemia/reperfusion (I/R). To test this, we evaluated SOD expression and activity, basal Superoxide production, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in kidneys from male and female wild-type (WT) and SOD3-knockout mice. RBF, measured using an ultrasonic flow probe, and histological indices of oxidative stress and injury were assessed after 1h of ischemia. Following ischemia, RBF was attenuated in kidneys from male, but not female, knockout mice compared with their WT counterparts. Total SOD activity was significantly reduced in male knockout compared with WT male mice but was similar in female mice of both genotypes, suggesting upregulated SOD1 activity. Basal Superoxide production and NADPH oxidase activity were unrelated to the differences in RBF. After 24h, kidneys from both genders of knockout mice were found to have more oxidative stress (3-nitrotyrosine immunohistochemistry) and renal cast formation than those from WT mice. Thus, our study found a key role for SOD3 in regulating renal I/R injury.

  • role of menkes atpase in angiotensin ii induced hypertension a key modulator for Extracellular Superoxide Dismutase function
    Hypertension, 2008
    Co-Authors: Zhenyu Qin, Tohru Fukai, Shinichi Itoh, Kiyoshi Ozumi, David G. Harrison, Masuko Ushiofukai, Maria Carolina Gongora, Kamran Akram
    Abstract:

    The Extracellular Superoxide Dismutase (SOD3), a secretory copper-containing enzyme, regulates angiotensin II (Ang II)-induced hypertension by modulating levels of Extracellular Superoxide anion. The present study was designed to determine the role of the copper transporter Menkes ATPase (MNK) in Ang II-induced SOD3 activity and hypertension in vivo. Here we show that chronic Ang II infusion enhanced systolic blood pressure and vascular Superoxide anion production in MNK mutant (MNK(mut)) mice as compared with those in wild-type mice, which are associated with impaired acetylcholine-induced endothelium-dependent vasorelaxation in MNK(mut) mice. These effects in MNK(mut) mice are rescued by infusion of the SOD mimetic Tempol. By contrast, norepinephrine-induced hypertension, which is not associated with an increase in vascular Superoxide anion production, is not affected in MNK(mut) mice. Mechanistically, basal and Ang II infusion-induced increase in vascular SOD3-specific activity is significantly inhibited in MNK(mut) mice. Coimmunoprecipitation analysis reveals that Ang II stimulation promotes association of MNK with SOD3 in cultured vascular smooth muscle cell and in mouse aortas, which may contribute to SOD3-specific activity by increasing copper delivery to SOD3 through MNK. In summary, MNK plays an important role in modulating Ang II-induced hypertension and endothelial function by regulating SOD3 activity and vascular Superoxide anion production and becomes a potential therapeutic target for oxidant stress-dependent cardiovascular diseases.

  • Extracellular Superoxide Dismutase ecsod in vascular biology an update on exogenous gene transfer and endogenous regulators of ecsod
    Translational Research, 2008
    Co-Authors: Zhenyu Qin, Tohru Fukai, Krzysztof J Reszka, Neal L Weintraub
    Abstract:

    Extracellular Superoxide Dismutase (ecSOD) is the major Extracellular scavenger of Superoxide (O 2 ·− ) and a main regulator of nitric oxide (NO) bioactivity in the blood vessel wall, heart, lungs, kidney, and placenta. Involvement of O 2 ·− has been implicated in many pathological processes, and removal of Extracellular O 2 ·− by ecSOD gene transfer has emerged as a promising experimental technique to treat vascular disorders associated with increased oxidant stress. In addition, recent studies have clarified mechanisms that regulate ecSOD expression, tissue binding, and activity, and they have provided new insight into how ecSOD interacts with other factors that regulate vascular function. Finally, studies of a common gene variant in humans associated with disruption of ecSOD tissue binding suggest that displacement of the enzyme from the blood vessel wall may contribute to vascular diseases. The purpose of this review is to summarize recent research findings related to ecSOD function and gene transfer and to stimulate other investigations into the role of this unique antioxidant enzyme in vascular pathophysiology and therapeutics.

David G. Harrison - One of the best experts on this subject based on the ideXlab platform.

  • role of vascular Extracellular Superoxide Dismutase in hypertension
    Hypertension, 2011
    Co-Authors: Heinrich E Lob, Antony Vinh, Yelena Blinder, Stefan Offermanns, David G. Harrison
    Abstract:

    Previous studies indicate that Superoxide is important in the modulation of blood pressure but have not specifically identified the cell types or organs involved. We created mice with loxP sites flanking the Extracellular Superoxide Dismutase (SOD3) gene. These mice were crossed with mice expressing inducible Cre-recombinase driven by the smooth muscle myosin heavy chain promoter allowing tissue-specific deletion of SOD3. Deletion of SOD3 increased vascular Superoxide and reduced vascular NO levels as detected by electron spin resonance. Despite these changes in NO and Superoxide, we did not observe increases in vascular inflammation caused by angiotensin II. Moreover, deletion of vascular SOD3 did not augment hypertension in response to angiotensin II. In additional studies, we also deleted SOD3 from the circumventricular organs by intracerebroventricular injection of an adenovirus encoding Cre-recombinase. Although this raised blood pressure and augmented the hypertension caused by angiotensin II, these responses were not further increased by vascular deletion of SOD3. These data suggest that the Extracellular Superoxide Dismutase in vascular smooth muscle is not involved in the genesis of angiotensin II-induced hypertension and further emphasize the role of central SOD3 in the modulation of blood pressure.

  • protective role of Extracellular Superoxide Dismutase in renal ischemia reperfusion injury
    Kidney International, 2010
    Co-Authors: Tohru Fukai, David G. Harrison, Markus P Schneider, Jennifer C Sullivan, Paul F Wach, Erika I Boesen, Tatsuo Yamamoto, David M Pollock, Jennifer S Pollock
    Abstract:

    Extracellular Superoxide Dismutase (SOD3) is highly expressed in renal tissues and a critical regulator of vascular function. We hypothesized that deletion of SOD3 would attenuate recovery of renal blood flow (RBF) and increase oxidative stress and injury following renal ischemia/reperfusion (I/R). To test this, we evaluated SOD expression and activity, basal Superoxide production, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in kidneys from male and female wild-type (WT) and SOD3-knockout mice. RBF, measured using an ultrasonic flow probe, and histological indices of oxidative stress and injury were assessed after 1h of ischemia. Following ischemia, RBF was attenuated in kidneys from male, but not female, knockout mice compared with their WT counterparts. Total SOD activity was significantly reduced in male knockout compared with WT male mice but was similar in female mice of both genotypes, suggesting upregulated SOD1 activity. Basal Superoxide production and NADPH oxidase activity were unrelated to the differences in RBF. After 24h, kidneys from both genders of knockout mice were found to have more oxidative stress (3-nitrotyrosine immunohistochemistry) and renal cast formation than those from WT mice. Thus, our study found a key role for SOD3 in regulating renal I/R injury.

  • induction of hypertension and peripheral inflammation by reduction of Extracellular Superoxide Dismutase in the central nervous system
    Hypertension, 2010
    Co-Authors: Heinrich E Lob, Louise Mccann, Paul J Marvar, Tomasz J Guzik, Shraya Sharma, Cornelia M Weyand, Frank J Gordon, David G. Harrison
    Abstract:

    The circumventricular organs (CVOs) lack a well-formed blood-brain barrier and produce Superoxide in response to angiotensin II and other hypertensive stimuli. This increase in central Superoxide has been implicated in the regulation of blood pressure. The Extracellular Superoxide Dismutase (SOD3) is highly expressed in cells associated with CVOs and particularly with tanycytes lining this region. To understand the role of SOD3 in the CVOs in blood pressure regulation, we performed intracerebroventricular injection an adenovirus encoding Cre-recombinase (5×108 particles per milliliter) in mice with loxP sites flanking the SOD3 coding region (SOD3loxp/loxp mice). An adenovirus encoding red-fluorescent protein was injected as a control. Deletion of CVO SOD3 increased baseline blood pressure modestly and markedly augmented the hypertensive response to low-dose angiotensin II (140 ng/kg per day), whereas intracerebroventricular injection of adenovirus encoding red-fluorescent protein had minimal effects on these parameters. Adenovirus encoding Cre-recombinase–treated mice exhibited increased sympathetic modulation of heart rate and blood pressure variability, increased vascular Superoxide production, and T-cell activation as characterized by increased circulating CD69+/CD3+ cells. Deletion of CVO SOD3 also markedly increased vascular T-cell and leukocyte infiltration caused by angiotensin II. We conclude that SOD3 in the CVO plays a critical role in the regulation of blood pressure, and its loss promotes T-cell activation and vascular inflammation, in part by modulating sympathetic outflow. These findings provide insight into how central signals produce vascular inflammation in response to hypertensive stimuli, such as angiotensin II.

  • role of menkes atpase in angiotensin ii induced hypertension a key modulator for Extracellular Superoxide Dismutase function
    Hypertension, 2008
    Co-Authors: Zhenyu Qin, Tohru Fukai, Shinichi Itoh, Kiyoshi Ozumi, David G. Harrison, Masuko Ushiofukai, Maria Carolina Gongora, Kamran Akram
    Abstract:

    The Extracellular Superoxide Dismutase (SOD3), a secretory copper-containing enzyme, regulates angiotensin II (Ang II)-induced hypertension by modulating levels of Extracellular Superoxide anion. The present study was designed to determine the role of the copper transporter Menkes ATPase (MNK) in Ang II-induced SOD3 activity and hypertension in vivo. Here we show that chronic Ang II infusion enhanced systolic blood pressure and vascular Superoxide anion production in MNK mutant (MNK(mut)) mice as compared with those in wild-type mice, which are associated with impaired acetylcholine-induced endothelium-dependent vasorelaxation in MNK(mut) mice. These effects in MNK(mut) mice are rescued by infusion of the SOD mimetic Tempol. By contrast, norepinephrine-induced hypertension, which is not associated with an increase in vascular Superoxide anion production, is not affected in MNK(mut) mice. Mechanistically, basal and Ang II infusion-induced increase in vascular SOD3-specific activity is significantly inhibited in MNK(mut) mice. Coimmunoprecipitation analysis reveals that Ang II stimulation promotes association of MNK with SOD3 in cultured vascular smooth muscle cell and in mouse aortas, which may contribute to SOD3-specific activity by increasing copper delivery to SOD3 through MNK. In summary, MNK plays an important role in modulating Ang II-induced hypertension and endothelial function by regulating SOD3 activity and vascular Superoxide anion production and becomes a potential therapeutic target for oxidant stress-dependent cardiovascular diseases.

  • role of Extracellular Superoxide Dismutase in hypertension
    Hypertension, 2006
    Co-Authors: Maria Carolina Gongora, Rodney J Folz, Ha Won Kim, Tohru Fukai, Zhenyu Qin, Karine Laude, Louise Mccann, Sergey Dikalov, David G. Harrison
    Abstract:

    We previously found that angiotensin II–induced hypertension increases vascular Extracellular Superoxide Dismutase (ecSOD), and proposed that this is a compensatory mechanism that blunts the hypertensive response and preserves endothelium-dependent vasodilatation. To test this hypothesis, we studied ecSOD-deficient mice. ecSOD −/− and C57Blk/6 mice had similar blood pressure at baseline; however, the hypertension caused by angiotensin II was greater in ecSOD −/− compared with wild-type mice (168 versus 147 mm Hg, respectively; P −/− than in wild-type mice. In contrast to these findings in resistance vessels, angiotensin II paradoxically improved endothelium-dependent vasodilatation, reduced intracellular and Extracellular Superoxide, and increased NO production in aortas of ecSOD −/− mice. Whereas aortic expression of endothelial NO synthase, Cu/ZnSOD, and MnSOD were not altered in ecSOD −/− mice, the activity of Cu/ZnSOD was increased by 80% after angiotensin II infusion. This was associated with a concomitant increase in expression of the copper chaperone for Cu/ZnSOD in the aorta but not in the mesenteric arteries. Moreover, the angiotensin II–induced increase in aortic reduced nicotinamide-adenine dinucleotide phosphate oxidase activity was diminished in ecSOD −/− mice as compared with controls. Thus, during angiotensin II infusion, ecSOD reduces hypertension, minimizes vascular Superoxide production, and preserves endothelial function in resistance arterioles. We also identified novel compensatory mechanisms involving upregulation of copper chaperone for Cu/ZnSOD, increased Cu/ZnSOD activity, and decreased reduced nicotinamide-adenine dinucleotide phosphate oxidase activity in larger vessels. These compensatory mechanisms preserve large vessel function when ecSOD is absent in hypertension.

Rodney J Folz - One of the best experts on this subject based on the ideXlab platform.

  • cpg methylation attenuates sp1 and sp3 binding to the human Extracellular Superoxide Dismutase promoter and regulates its cell specific expression
    Free Radical Biology and Medicine, 2010
    Co-Authors: Igor N Zelko, Michael Rolf Mueller, Rodney J Folz
    Abstract:

    Extracellular Superoxide Dismutase (EC-SOD) plays an important role in maintaining normal redox homeostasis in the lung. It is expressed at very high levels in pulmonary fibroblasts, alveolar type II epithelial cells, and smooth muscle cells. The molecular mechanisms governing this cell-specific expression of EC-SOD are mostly unknown. In our previous studies we showed that EC-SOD cell-specific expression was not attributable to differential transcriptional regulation, suggesting that other, possibly epigenetic, mechanisms are involved in regulation of its expression. In this paper, we show high levels of promoter methylation in A549 cells and correspondingly low levels of methylation in MRC5 cells. Inhibition of DNA methyltransferase activity by 5-azacytidine in A549 cells reactivated EC-SOD transcription (2.75+/-0.16-fold, P<0.001), demonstrating the importance of methylation in the repression of EC-SOD expression. Furthermore, methylation of cytosines in the promoter markedly decreased Sp1/Sp3-driven promoter activity to 30.09+/-2.85% (P<0.001) compared to unmethylated promoter. This attenuation of transcription of the promoter/reporter construct was, at least in part, attributable to the binding of the methyl-binding protein MeCP2 in the insect cells. However, no binding of MeCP2 or MBD2 protein to the EC-SOD promoter was detected in mammalian cells in vivo. We also found marked differences in the chromatin organization of the EC-SOD promoter between these two cell lines, further supporting the important role epigenetic modifications play in the regulation of EC-SOD expression.

  • role of Extracellular Superoxide Dismutase in hypertension
    Hypertension, 2006
    Co-Authors: Maria Carolina Gongora, Rodney J Folz, Ha Won Kim, Tohru Fukai, Zhenyu Qin, Karine Laude, Louise Mccann, Sergey Dikalov, David G. Harrison
    Abstract:

    We previously found that angiotensin II–induced hypertension increases vascular Extracellular Superoxide Dismutase (ecSOD), and proposed that this is a compensatory mechanism that blunts the hypertensive response and preserves endothelium-dependent vasodilatation. To test this hypothesis, we studied ecSOD-deficient mice. ecSOD −/− and C57Blk/6 mice had similar blood pressure at baseline; however, the hypertension caused by angiotensin II was greater in ecSOD −/− compared with wild-type mice (168 versus 147 mm Hg, respectively; P −/− than in wild-type mice. In contrast to these findings in resistance vessels, angiotensin II paradoxically improved endothelium-dependent vasodilatation, reduced intracellular and Extracellular Superoxide, and increased NO production in aortas of ecSOD −/− mice. Whereas aortic expression of endothelial NO synthase, Cu/ZnSOD, and MnSOD were not altered in ecSOD −/− mice, the activity of Cu/ZnSOD was increased by 80% after angiotensin II infusion. This was associated with a concomitant increase in expression of the copper chaperone for Cu/ZnSOD in the aorta but not in the mesenteric arteries. Moreover, the angiotensin II–induced increase in aortic reduced nicotinamide-adenine dinucleotide phosphate oxidase activity was diminished in ecSOD −/− mice as compared with controls. Thus, during angiotensin II infusion, ecSOD reduces hypertension, minimizes vascular Superoxide production, and preserves endothelial function in resistance arterioles. We also identified novel compensatory mechanisms involving upregulation of copper chaperone for Cu/ZnSOD, increased Cu/ZnSOD activity, and decreased reduced nicotinamide-adenine dinucleotide phosphate oxidase activity in larger vessels. These compensatory mechanisms preserve large vessel function when ecSOD is absent in hypertension.

  • overexpression of Extracellular Superoxide Dismutase reduces acute radiation induced lung toxicity
    BMC Cancer, 2005
    Co-Authors: Zahid N Rabbani, Rodney J Folz, Mitchell S Anscher, Emerald Archer, Hong Huang, L Chen, Maria L Golson, T Samulski, Mark W Dewhirst, Zeljko Vujaskovic
    Abstract:

    Acute RT-induced damage to the lung is characterized by inflammatory changes, which proceed to the development of fibrotic lesions in the late phase of injury. Ultimately, complete structural ablation will ensue, if the source of inflammatory / fibrogenic mediators and oxidative stress is not removed or attenuated. Therefore, the purpose of this study is to determine whether overexpression of Extracellular Superoxide Dismutase (EC-SOD) in mice ameliorates acute radiation induced injury by inhibiting activation of TGFβ1 and downregulating the Smad 3 arm of its signal transduction pathway. Whole thorax radiation (single dose, 15 Gy) was delivered to EC-SOD overexpressing transgenic (XRT-TG) and wild-type (XRT-WT) animals. Mice were sacrificed at 1 day, 1 week, 3, 6, 10 and 14 weeks. Breathing rates, right lung weights, total/differential leukocyte count, activated TGFβ1 and components of its signal transduction pathway (Smad 3 and p-Smad 2/3) were assessed to determine lung injury. Irradiated wild-type (XRT-WT) animals exhibited time dependent increase in breathing rates and right lung weights, whereas these parameters were significantly less increased (p < 0.05) at 3, 6, 10 and 14 weeks in irradiated transgenic (XRT-TG) mice. An inflammatory response characterized predominantly by macrophage infiltration was pronounced in XRT-WT mice. This acute inflammation was significantly attenuated (p < 0.05) in XRT-TG animals at 1, 3, 6 and 14 weeks. Expression of activated TGFβ1 and components of its signal transduction pathway were significantly reduced (p < 0.05) at later time-points in XRT-TG vs. XRT-WT. This study shows that overexpression of EC-SOD confers protection against RT-induced acute lung injury. EC-SOD appears to work, in part, via an attenuation of the macrophage response and also decreases TGFβ1 activation with a subsequent downregulation of the profibrotic TGFβ pathway.

  • Extracellular Superoxide Dismutase protects lung development in hyperoxia exposed newborn mice
    American Journal of Respiratory and Critical Care Medicine, 2003
    Co-Authors: Mohamed Ahmed, Hagir B. Suliman, Rodney J Folz, Maria L Golson, Eva Nozikgrayck, Nicholas S Mason, Richard L Auten
    Abstract:

    We tested the hypothesis that targeted transgenic overexpression of human Extracellular Superoxide Dismutase (EC-SOD) would preserve alveolar development in hyperoxia-exposed newborn mice. We exposed newborn transgenic and wild-type mice to 95% oxygen (O2) or air × 7 days and measured bronchoalveolar lavage cell counts, and lung homogenate EC-SOD, oxidized and reduced glutathione, and myeloperoxidase. We found that total EC-SOD activity in transgenic newborn mice was approximately 2.5× the wild-type activity. Hyperoxia-exposed transgenic mice had less pulmonary neutrophil influx and oxidized glutathione than wild-type littermates at 7 days. We measured alveolar surface and volume density in animals exposed to 14 days more of air or 60% O2. Hyperoxia-exposed transgenic EC-SOD mice had significant preservation of alveolar surface and volume density compared with wild-type littermates. After 7 days 95% O2 + 14 days 60% O2, lung inflammation measured as myeloperoxidase activity was reduced to control levels i...

  • overexpression of Extracellular Superoxide Dismutase protects mice from radiation induced lung injury
    International Journal of Radiation Oncology Biology Physics, 2002
    Co-Authors: Song K Kang, Rodney J Folz, Zahid N Rabbani, Mitchell S Anscher, Hong Huang, Maria L Golson, T Samulski, Mark W Dewhirst, Zeljko Vujaskovic
    Abstract:

    Abstract Purpose The purpose of this study was to determine if radiation-induced lung injury is associated with prolonged oxidative stress, and whether chronic overexpression of Extracellular Superoxide Dismutase (EC-SOD) in the lung of transgenic mice protects against radiation-induced lung injury. Methods and materials Whole-lung radiation was delivered to EC-SOD overexpressing B6C3 transgenic (XRT-TG) mice and wild-type littermates (XRT-WT). Pulmonary function was assessed by breathing frequency. Right lung wet weight was used as a gross indicator of lung damage. Histopathology was used to assess collagen deposition and tissue fibrosis according to an established grading system. Immunohistochemistry was used to stain and quantify the number of macrophages. ELISA was used to measure activated TGF-β1. Oxidative stress was assessed by measuring lipid oxidation products (malondialic acid) by HPLC. Results Four of six XRT-WT mice required euthanasia at 15–19 weeks postradiation because of respiratory distress, whereas no XRT-TG mouse developed distress. All assessments of lung damage at 15–20 weeks postradiation were higher for XRT-WT mice compared with the XRT-TG mice, including breathing frequency (380 vs. 286 bpm, p ≤ 0.0004), right lung weight (228 vs. 113 mg, p ≤ 0.06), macrophage count (48 vs. 5 per 40× field, p ≤ 0.06), and percent activated TGF-β1 (37 vs. 11%, p ≤ 0.06). Semiquantitative measures, including fibrosis and collagen deposition, were also higher for XRT-WT mice, with an exact Fisher p value of ≤0.03 for both variables. In addition, malondialic acid was elevated in XRT-WT mice 15–20 weeks after radiation delivery, and levels were lower in the XRT-TG mice (624 vs. 323 pmol/mg protein, p ≤ 0.06). Conclusions After radiation therapy, oxidative stress is present at 15–20 weeks after initial exposure, which correlates with the delayed clinical onset of radiation-induced lung damage. Overexpression of EC-SOD in transgenic mice appears to confer protection against this radiation-induced lung injury, with a corresponding decrease in oxidative stress. EC-SOD may be a potential therapeutic agent for radioprotection in the treatment of thoracic malignancies. Further investigation is needed to confirm and expand on the current results.

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