Role Of Manganese Superoxide Dismutase Research Articles

Manganese Enhances the Osteogenic Effect of Silicon-Hydroxyapatite Nanowires by Targeting T Lymphocyte Polarization.

Biomaterials encounter considerable challenges in extensive bone defect regeneration. The amelioration of outcomes may be attainable through the orchestrated modulation of both innate and adaptive immunity. Silicon-hydroxyapatite, for instance, which solely focuses on regulating innate immunity, is inadequate for long-term bone regeneration. Herein, extra manganese (Mn)-doping is utilized for enhancing the osteogenic ability by mediating adaptive immunity. Intriguingly, Mn-doping engenders heightened recruitment of CD4+ T cells to the bone defect site, concurrently manifesting escalated T helper (Th) 2 polarization and an abatement in Th1 cell polarization. This consequential immune milieu yields a collaborative elevation of interleukin 4, secreted by Th2 cells, coupled with attenuated interferon gamma, secreted by Th1 cells. This orchestrated interplay distinctly fosters the osteogenesis of bone marrow stromal cells and effectuates consequential regeneration of the mandibular bone defect. The modulatory mechanism of Th1/Th2 balance lies primarily in the indispensable role of manganese superoxide dismutase (MnSOD) and the phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK). In conclusion, this study highlights the transformative potential of Mn-doping in amplifying the osteogenic efficacy of silicon-hydroxyapatite nanowires by regulating T cell-mediated adaptive immunity via the MnSOD/AMPK pathway, thereby creating an anti-inflammatory milieu favorable for bone regeneration.

Manganese Superoxide Dismutase as a Novel Oxidative Stress Biomarker for Predicting Paroxysmal Atrial Fibrillation.

Background: There is accumulating evidence indicating that inflammation and oxidative stress are involved in the pathogenesis of atrial fibrillation (AF). The role of manganese superoxide dismutase (MnSOD) in the initiation and maintenance of AF has not yet been well characterized. The aim of our study is to investigate whether or not plasma MnSOD levels are associated with AF. Methods: We enrolled a total of 130 consecutive patients with AF as the case group (paroxysmal AF: 87, persistent AF: 43) and 58 patients without a history of AF as the control group after screening. Baseline clinical characteristics, laboratory and echocardiographic parameters were collected. Plasma levels of nicotinamide-adenine dinucleotide phosphate oxidase 4 (NOX4) and MnSOD were measured by an enzyme-linked immunosorbent assay (ELISA) method. These data were compared between the different groups. The relationship between MnSOD and other parameters was assessed using Spearman correlation. Multivariable logistic regression analysis was performed to identify independent predictors of AF. The area under the curve (AUC) from receiver operating characteristics (ROC) analysis was constructed to explore the value of MnSOD in predicting the occurrence of AF. Results: The levels of MnSOD were the highest in the paroxysmal AF group, followed by the persistent AF group, and the lowest in the controls. Meanwhile, the levels in the paroxysmal AF group were significantly higher than those in the controls [322.84 (165.46, 547.61) vs. 201.83 (129.53, 301.93), p = 0.002], but no significant difference was found between the paroxysmal AF group and persistent AF group, as well as the persistent AF group and the controls. Spearman correlation analysis indicated that there was a significantly negative correlation between MnSOD levels and LAD (r = −0.232, p = 0.008) and a positive correlation between MnSOD levels and RDW-CV (r = 0.214, p = 0.014) in the case group. Multivariate logistic regression analysis indicated that MnSOD levels [odds ratio (OR): 1.003, 95% confidence interval (CI): 1.001–1.005, p = 0.002] were an independent risk factor for paroxysmal AF, and the best cut-off value of MnSOD in predicting paroxysmal AF gained by ROC curve analysis was 311.49 ug/mL (sensitivity of 52.9%, specificity of 77.6%, AUC = 0.668). Conclusion: Oxidative stress underlies the pathogenesis of AF and may play a stronger role in paroxysmal AF than persistent AF. Our study showed an independent association between increased circulating plasma MnSOD levels and the occurrence of paroxysmal AF.

Manganese superoxide dismutase induced by lipoteichoic acid isolated from Staphylococcus aureus regulates cytokine production in THP-1cells.

Lipoteichoic acid isolated from Staphylococcus aureus (aLTA) is known to regulate the production of pro-inflammatory cytokines through TLR2-mediated signaling pathways. In our previous study, we found that aLTA significantly increased manganese superoxide dismutase (MnSOD) in the THP-1 human monocyte-like cell line, but the role of MnSOD in the regulation of cytokine production was not elucidated. In the current study, we found that MnSOD was involved in aLTA-mediated cytokine production. The signaling pathways associated with aLTA-mediated MnSOD induction in THP-1cells included TLR2-MyD88-IRAK2, JNK (c-Jun N-terminal kinases)1/2 and nuclear factor- κB (NF-κB). We also found MnSOD was involved in the regulation of IL-1β and TNF-α, which were induced by early signaling pathways, including JNK1/2, p38, and NF-κB p65. In addition, MnSOD was also involved in the production of IL-6 and CCL2 in aLTA-stimulated THP-1cells through activation of late signaling pathways such as JAK2-STAT3. Taken together, our data suggest that aLTA-mediated MnSOD production involved in the regulation of cytokine production and it may be the cause of one of the excessive inflammatory reactions caused by S. aureus.

ACTIVITY OF MITOCHONDRIAL ANTIOXIDANT DEFENSE SYSTEM IN YOUNG PATIENTS WITH GASTROESOPHAGEAL REFLUX DISEASE

Background. Despite numerous studies, the pathogenesis of gastroesophageal reflux disease remains unclear. Aim of research: assessment the activity of antioxidant defense system in young patients with GERD based on expression of biomarker associated with mitochondrial function. Material and methods. The study included 45 patients with gastroesophageal reflux disease. The examined contingent was presented by students age from 18 to 25 years. 20 healthy persons were included as control group. Levels of manganese superoxide dismutase were determined in blood serum of study persons with enzyme immunoassays (ELISA, Elabscience, USA). Statistical data processing by the Statistica Basic Academic 13 for Windows En local was made. Results. Gastroesophageal reflux disease in young patients is characterized by significantly increasing of manganese superoxide dismutase as compare to control group (7.1700 ng/ml vs 4.4720 ng/ml respectively, p<0.01). Presence of erosion in esophagus mucous doesn't accompanied by significant changes of evaluated parameter as compare with non-erosion form of disease in patients. Conclusion. The elevation in young patients with GERD the biomarker of mitohondrial antioxidant defense system we may speculate as adaptive response contributing to non-specific citoprotection. Taking to account the publishing facts about dual role of manganese superoxide dismutase it is necessary to monitoring antioxidant enzyme in patients with gastroesophageal reflux disease for prediction of possible complications and outcome.

Role of manganese superoxide dismutase (Mn-SOD) against Cr(III)-induced toxicity in bacteria

The toxicity of Cr(VI) was widely investigated, but the defense mechanism against Cr(III) in bacteria are seldom reported. Here, we found that Cr(III) inhibited bacterial growth and induced reactive oxygen species (ROS). After exposure to Cr(III), loss of sodA not only led to the excessive generation of ROS, but also enhanced the level of lipid peroxidation and reduced the GSH level, indicating that the deficiency of Mn-SOD decreased the bacterial resistance ability against Cr(III). The adverse effects of oxidative stress caused by Cr(III) could be recovered by the rescue of Mn-SOD in the sodA-deficient strain. Besides the oxidative stress, Cr(III) could cause the bacterial morphology variation, which was distinct between the wild-type and the sodA-deficient strains due to the differential expressions of Z-ring division genes. Moreover, Mn-SOD might prevent Cr(III) from oxidation on the bacterial surface by combining with Cr(III). Taken together, our results indicated that the Mn-SOD played a vital role in regulating the stress resistance, expression of cell division-related genes, bacterial morphology, and chemistry valence state of Cr. Our findings firstly provided a more in-depth understanding of Cr(III) toxicity and bacterial defense mechanism against Cr(III).

Role of MnSOD Val16Ala Gene Polymorphism in Changing the Level of Serum Metals in Workers Exposed to Heavy Metals in Al-Nasiriyah City

Low activity of antioxidant enzymes due to polymorphism in antioxidant genes and differences in mineral and metal levels creates oxidative stress that may play a role in advancing many diseases. The aim of this study was to determine the role of Manganese superoxide dismutase (MnSOD) gene polymorphism [rs4880 Val16Ala)] in exposed workers and to compare the levels of metals and minerals among its various genotypes in control group. A total of 80 individuals including age and gender matched workers and control group were genotyped. Detection of rs4880 polymorphism was done using sequencing technique. The blood serum were tested for determination of metals and minerals using Atomic absorption spectrophotometer (AA 6600 Shimadzu). This study indicate that the frequency of T allele was higher than that of C allele in control group as well as in workers. Our results indicate no association between all genotypes in study subjects. The results of present study indicates that Pb and Cd concentration differ significantly between TT genotypes of MnSOD (rs4880) gene polymorphism as compared to CC genotypes in workers and control group (p<0.05). Control group with TT, TC and CC genotypes have high concentration of Fe, Cu and Zn as compared to workers group.

Abstract 116: A Novel Mediator of Heart Failure Development and Progression- Role of Manganese Superoxide Dismutase

Manganese Superoxide Dismutase (MnSOD), an antioxidant enzyme that catalyzes the conversion of superoxide radicals (O 2 •- ) in mitochondria. Constitutive activation mitochondrial reactive oxygen species (ROS) has been implicated in both the pathogenesis and the progression of cardiovascular disease. Absence of SOD2 (gene that encodes MnSOD) is found to be embryonic lethal in animal models due to impairment of mitochondrial function, most noticeably in the heart. In our earlier investigation, we have shown that the MnSOD mimetic, MnTnBuOE-2-PyP 5+ distributes 3-fold more in mitochondria than in cytosol. The exceptional ability of MnTnBuOE-2-PyP 5+ to dismute O 2 •- parallels its ability to reduce ONOO– and CO3–. Based on our earlier reports, we have generated mice that specifically lack MnSOD in cardiomyocytes (Myh6-SOD2 Δ ). These mice showed early mortality ~4 months due to cardiac mitochondrial dysfunction. Oxidative phosphorylation (OXPHOS) in mitochondria is the predominant mode for O 2 consumption in cells, and the mitochondria are the primary source of ROS in cells due to leaked electrons. FACS analyses using Mito-Tracker Green indicated that the mass of mitochondria per cell was slightly decreased in the Myh6-SOD2 Δ to the wild type. We then examined OXPHOS levels in Myh6-SOD2 Δ v.s. Wild type using a Seahorse XF analyzer. The rate of oxygen consumption per cells was significantly lower in Myh6-SOD2 Δ cardiomyocytes than that in wild type. The most noticeable difference in the O 2 consumption was found in the presence of FCCP (H + ionophore / uncoupler). FCCP is an inner membrane pore opener which resets the proton gradient between the mitochondrial matrix and the interspace, resulting in continuous transport of protons and consuming O 2 at the maximum potential. Remarkably, while the FCCP treatment increased O 2 consumption in wild type, the treatment showed no effect on the O 2 consumption in the Myh6-SOD2 Δ cardiomyocytes. The result indicated that the low basal OXPHOS activity in Myh6-SOD2 Δ was due to unusually low OXPHOS potential. We examined glycolysis in these cells by measuring extracellular acidification (ECAR) and the pattern exactly opposite to that of oxygen consumption rate (OCR) was observed for glycolysis rates between Myh6-SOD2 Δ and Wild type.

Differential Regulation of Proteins and a Possible Role for Manganese Superoxide Dismutase in Bioluminescence of &amp;lt;i&amp;gt;Panellus stipticus&amp;lt;/i&amp;gt; Revealed by Suppression Subtractive Hybridization

Suppression subtractive hybridization (SSH) was employed to investigate bioluminescence in Panellus stipticus (Bull.) P. Karst. by detecting proteins differentially expressed in bioluminescent and luminescent strains. Comparisons of luminescent and non-luminescent monokaryon cultures of North American strains revealed differences in transcript levels of proteins responsible for post-translational modification (PTM) of enzymes. A similar comparison of a luminescent strain of P. stipticus from North America with a non-luminescent European strain revealed the presence of extracellular manganese superoxide dismutase (MnSOD) in the luminescent form, in addition to proteins involved in PTM. The application of MnSOD-specific inhibitors to luminescent mycelium resulted in the rapid loss of luminescence. The relevance to luminescence of proteins involved in PTM is discussed, together with a possible role for MnSOD that considers the potential for SODs to form stable complexes with catechols revealed in previously published research. In light of the recent discovery that hispidine may be the precursor of fungal luciferin, we consider a hypothetical mechanism for fungal luminescence in which the ο-hydroquinone moiety of a hispidine derivative ligates with the extracellular form of MnSOD producing a semiquinone-radical complex, with the resultant semiquinonato complex potentially reacting with molecular oxygen or other reactive oxygen species to produce sufficiently excited intermediates to emit light on relaxation.

Theaflavin-3,3′-digallate, a black tea polyphenol, stimulates lipolysis associated with the induction of mitochondrial uncoupling proteins and AMPK–FoxO3A–MnSOD pathway in 3T3-L1 adipocytes

Phytochemicals have gained an immense interest in obesity management. Previously, we have shown that theaflavin-3,3′-digallate (TF3), a black tea polyphenol, prevents adipocyte-triggered metaflammation. Here, we demonstrate that TF3 attenuates triacylglycerol accumulation in adipocytes, concomitant with promoting gene expression profile that favors lipolysis and β-oxidation, and inducing energy dissipation-related genes, mitochondrial uncoupling protein-1 (UCP-1) and UCP-2. The gene expression is in line with the upregulation of peroxisome proliferator-activated receptor α (PPARα), a primary transactivator for the expression of lipolytic genes. TF3 activates AMP-activated protein kinase (AMPK), which is required for TF3 effects of PPARα upregulation, and the reversal of the inactivation of Forkhead-box-O 3A (FoxO3A) and insulin-induced suppression of manganese superoxide dismutase (MnSOD). The role of MnSOD in adipogenesis is verified in MnSOD-overexpressing adipocytes. Thus, our results demonstrate TF3 as a potent AMPK activator with anti-adiposity activity in adipocytes, suggesting its potential application in functional foods and nutraceuticals for obesity management.

Manganese Superoxide Dismutase Is a Promising Target for Enhancing Chemosensitivity of Basal-Like Breast Carcinoma

Although earlier reports highlighted a tumor suppressor role for manganese superoxide dismutase (MnSOD), recent evidence indicates increased expression in a variety of human cancers including aggressive breast carcinoma. In the present article, we hypothesized that MnSOD expression is significantly amplified in the aggressive breast carcinoma basal subtype, and targeting MnSOD could be an attractive strategy for enhancing chemosensitivity of this highly aggressive breast cancer subtype. Using MDA-MB-231 and BT549 as a model of basal breast cancer cell lines, we show that knockdown of MnSOD decreased the colony-forming ability and sensitized the cells to drug-induced cell death, while drug resistance was associated with increased MnSOD expression. In an attempt to develop a clinically relevant approach to down-regulate MnSOD expression in patients with basal breast carcinoma, we employed activation of the peroxisome proliferator-activated receptor gamma (PPARγ) to repress MnSOD expression; PPARγ activation significantly reduced MnSOD expression, increased chemosensitivity, and inhibited tumor growth. Moreover, as a proof of concept for the clinical use of PPARγ agonists to decrease MnSOD expression, biopsies derived from breast cancer patients who had received synthetic PPARγ ligands as anti-diabetic therapy had significantly reduced MnSOD expression. Finally, we provide evidence to implicate peroxynitrite as the mechanism involved in the increased sensitivity to chemotherapy induced by MnSOD repression. These data provide evidence to link increased MnSOD expression with the aggressive basal breast cancer, and underscore the judicious use of PPARγ ligands for specifically down-regulating MnSOD to increase the chemosensitivity of this subtype of breast carcinoma.

The role of Mn-SOD and Fe-SOD genes in the response to low temperature in chs mutants of Arabidopsis

To determine whether the expression of iron superoxide dismutase (Fe-SOD) and manganese superoxide dismutase (Mn-SOD) increase superoxide-scavenging capacity, and thereby improve the survival rate of chilling sensitive (chs) mutants of Arabidopsis, 4 chs mutant (chs1-1, chs1-2, chs2-1, and chs2-2) and wild-type plants were grown under low (chilling, 13 °C; cold, 4 °C) and normal growth (23 °C) temperatures. Photosynthetic parameters were investigated following treatment with chilling, cold, and normal growth conditions. Chlorophyll content and maximum quantum efficiency of PSII primary photochemistry (Fv/Fm) were reduced in plants grown at chilling stress. The degree of chilling sensitivity of chs1 mutant plants was significantly greater than that of wild-type and chs2 mutants, as measured by chlorophyll fluorescence value and chlorophyll content. MSD1 was expressed during chilling stress in chs mutant and WT plants, while expression of FSD2 and FSD3 SODs in chs mutants was not detected during any of the treatments. Our results suggest that MSD1 expression in chs1-chilled plants responds to chilling, and that the lack of expression of FSD2 and FSD3 genes in chs mutants grown at chilling temperature supports the hypothesis that chloroplasts might be damaged, due to the chs mutation, when they are chilled.

Analysis of manganese superoxide dismutase (MnSOD: Ala-9Val) and glutathione peroxidase (GSH-Px: Pro 197 Leu) gene polymorphisms in mood disorders.

We investigated the etiopathogenetic role of manganese superoxide dismutase (MnSOD) (Ala-9Val) and glutathione peroxidase (GSH-Px) (Pro 197 Leu) gene polymorphisms in patients diagnosed with major depressive disorder (MDD) and bipolar I disorder (BD). Eighty patients with MDD, 82 patients with BD (total 162 patients) and 96 healthy controls were enrolled in this study and genotyped using a Real Time-Quantitative Polymer Chain Reaction (RT-qPCR)-based method. The patients with BD and MDD and the controls had a similar distribution of the genotypes and alleles in the Ala-9Val MnSOD gene polymorphism. Comparison of the MDD group and control group regarding the Pro 197 Leu GSH-Px gene polymorphism revealed similar genotype distribution but different allele distribution. The BD group and control group were similar both for genotypes and for alleles when compared regarding the Pro 197 Leu GSH-Px gene polymorphism. The combined analysis (MDD plus BD) also failed to find any association between the Ala-9Val MnSOD and Pro 197 Leu GSH-Px gene polymorphism. Although small statistical power of the current study the significant difference between patients with depression and the control group for the Pro 197 Leu GSH-Px polymorphism indicates that the distribution of these alleles may have a contribution in the physiopathogenesis of depression. One of the limitation of the current study is that the sample size is too small. Understanding of the exact role of Pro 197 Leu GSH-Px polymorphism in the development of depression needs to further studies with more sample size and high statistical power.

P53 Regulation of Energy Metabolism and Mitochondria Regulation of p53 in Cancer Cells: An Insight into the Role of Manganese Superoxide Dismutase

Accumulated evidence suggests that p53 plays an important role in the regulation of metabolism and intracellular redox homeostasis through transcription-dependent and -independent mechanisms. Mitochondria, the power plant of cells, provide cells with ATP for their functions by regulating energy metabolism. In addition, as the byproducts of metabolism, reactive oxygen species (ROS) generated in the mitochondria can serve as signaling molecules to regulate p53 function. The regulation of p53 by mitochondria, especially redox-mediated regulation, may be involved in controlling the cellular switch between survival and death. The interplay between p53 and manganese superoxide dismutase (MnSOD), an important mitochondrial antioxidant enzyme, is an example of how nuclear and mitochondrial p53 coordinate their response to different levels of stress and contribute to the fate of cells.

Characterization of Superoxide Dismutases in Cardiac Progenitor Cells Demonstrates a Critical Role for Manganese Superoxide Dismutase

Transplantation of cardiac progenitor cells (CPCs) is currently in early clinical testing as a potential therapeutic strategy. Superoxide is increased in the ischemic myocardium and poor survival of cells is one of the major limitations of cell transplantation therapy. Superoxide dismutase (SOD) levels were analyzed in c-kit-positive CPCs isolated from rat myocardium to identify their roles in protection against oxidative stress-induced apoptosis in vitro. CPCs were subjected to oxidative stress using xanthine/xanthine oxidase (XXO) and little apoptosis was detected. CPCs contained significantly higher levels of SOD1 and SOD2 as compared with adult cardiac cell types, both at the protein and activity levels. Both SOD1 and SOD2 were increased by XXO at the mRNA and protein level, suggesting compensatory adaptation. Only knockdown of SOD2 and not SOD1 with siRNA sensitized the cells to XXO-apoptosis, despite only accounting for 10% of total SOD levels. Finally, we found XXO activated Akt within 10 min, and this regulated both SOD2 gene expression and protection against apoptosis. Rat CPCs are resistant to superoxide-induced cell death, primarily through higher levels of SOD2 compared to adult cardiac-derived cells. Exposure to superoxide increases expression of SOD2 in an Akt-dependent manner and regulates CPC survival during oxidative stress.

The role of manganese superoxide dismutase in skin aging

The free radical theory of aging postulates that the production of mitochondrial reactive oxygen species is the major determinant of aging and lifespan. The skin represents an excellent and accessible model organ to study aging that is characterized by atrophy, wrinkle formation, reduced tensile strength and impaired wound healing. Oxidative stress as a consequence of an imbalance in prooxidants and antioxidants with increased ROS concentrations has been demonstrated in the aged skin in vitro and in vivo, suggesting the important role of the antioxidant balance. Here we will summarize recent data on the role of the mitochondrial superoxide dismutase 2 in skin aging.

Abstract A175: Role of MnSOD and hydrogen peroxide in rapamycin-induced cytostasis.

Abstract Existing treatments for mantle cell lymphoma (MCL) are non-curative, demonstrating a need for a refined treatment approach. Recent clinical trials have shown promising results with the use of mammalian target of rapamycin (mTOR) inhibitors. While cyclin D1 can be regulated through the mTOR pathway, treatment with mTOR inhibitors often inhibits MCL growth without altering cyclin D1 levels of expression. Thus, the anti-tumor activity of mTOR inhibitors is likely mediated through other key targets. In other malignancies, recent data suggests that increased oxidative stress plays a role in the growth suppressive mechanisms of mTOR inhibitors. Initial studies in our lab indicated that a 48 hour rapamycin treatment of MCL cell lines increased overall levels of reactive oxygen species (ROS). Specifically, we found evidence of increased hydrogen peroxide (H2O2) levels in the cells. One potential source of H2O2 is manganese superoxide dismutase (MnSOD), which is a known tumor suppressor in several cell types. MnSOD catalyzes the dismutation of superoxide to H2O2 in the mitochondria. Thus, it removes one form of ROS while generating another. We hypothesized that the anti-tumor effect of mTOR inhibitors in MCL is mediated by an accumulation of ROS, specifically H2O2, due to an increase in MnSOD protein expression. We investigated the effect of a 48 hour rapamycin treatment on MnSOD in two MCL cell lines and genetic manipulation of MnSOD in Jurkat cells, a T lymphocyte cell line. Rapamycin treatment increased MnSOD in the MCL cell lines as well as Jurkat cells. Overall, sensitivity of cells to rapamycin correlated with high MnSOD levels. Analysis of the results showed that rapamycin treatment increased MnSOD expression in parallel with H2O2. Over-expression of MnSOD in Jurkat cells elevated the level of H2O2 and resulted in a cytotoxic, rather than cytostatic, effect of rapamycin. Treatment with the general ROS scavenger, N-acetyl cysteine, reduced overall ROS, cellular levels of H2O2, and the growth inhibitory effect of rapamycin. These findings indicate that the rapamycin-induced cytostatic effect is characterized by increased levels of MnSOD and H2O2, which is necessary for the full growth inhibitory effect of rapamycin. Rapamycin and its derivatives are generally well accepted as inhibitors of the mTORC1 complex upon initial treatment, but recent studies in other cell lines have shown that long term treatment can have an inhibitory effect on the mTORC2 complex and its downstream targets, such as Akt. Our results found that treatment with rapamycin resulted in a loss of S473 phosphorylation of Akt in the MCL cell lines. Increased levels of MnSOD following treatment of Jurkat cells were found to be due to inhibition of the mTORC2 complex. These results suggest that in MCL cells treated with rapamycin for 48 hours the mTORC2 complex is inhibited. Multiple transcription factors that have been linked to MnSOD regulation are affected by the Akt pathway. By understanding the key signaling molecules and affected pathways in the anti-tumor effects of rapamycin, we may be able to identify additional predictive markers to improve the therapeutic value of mTOR inhibitors, or study drug combinations that will enhance the effect of ROS-induced cytotoxicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A175.

Manganese superoxide dismutase inhibits neointima formation through attenuation of migration and proliferation of vascular smooth muscle cells

Superoxide anion is elevated during neointima development and is essential for neointimal vascular smooth muscle cell (VSMC) proliferation. However, little is known about the role of manganese superoxide dismutase (MnSOD, SOD2) in the neointima formation following vascular injury. SOD2 in the mitochondria plays an important role in cellular defense against oxidative damage. Because of its subcellular localization, SOD2 is considered the first line of defense against oxidative stress and plays a central role in metabolizing superoxide. Because mitochondria are the most important sources of superoxide anion, we speculated that SOD2 may have therapeutic benefits in preventing vascular remodeling. In this study, we used a rat carotid artery balloon-injury model and an adenoviral gene delivery approach to test the hypothesis that SOD2 suppresses vascular lesion formation. SOD2 was activated along with the progression of neointima formation in balloon-injured rat carotid arteries. Depletion of SOD2 by RNA interference markedly promoted the lesion formation, whereas SOD2 overexpression suppressed the injury-induced neointima formation via attenuation of migration and proliferation of VSMCs. SOD2 exerts its inhibitory effect on VSMC migration induced by angiotensin II by scavenging superoxide anion and suppressing the phosphorylation of Akt. Our data indicate that SOD2 is a negative modulator of vascular lesion formation after injury. Therefore, SOD2 augmentation may be a promising therapeutic strategy for the prevention of lesion formation in proliferative vascular diseases such as restenosis.

The role of manganese superoxide dismutase in inflammation defense.

Antioxidant enzymes maintain cellular redox homeostasis. Manganese superoxide dismutase (MnSOD), an enzyme located in mitochondria, is the key enzyme that protects the energy-generating mitochondria from oxidative damage. Levels of MnSOD are reduced in many diseases, including cancer, neurodegenerative diseases, and psoriasis. Overexpression of MnSOD in tumor cells can significantly attenuate the malignant phenotype. Past studies have reported that this enzyme has the potential to be used as an anti-inflammatory agent because of its superoxide anion scavenging ability. Superoxide anions have a proinflammatory role in many diseases. Treatment of a rat model of lung pleurisy with the MnSOD mimetic MnTBAP suppressed the inflammatory response in a dose-dependent manner. In this paper, the mechanisms underlying the suppressive effects of MnSOD in inflammatory diseases are studied, and the potential applications of this enzyme and its mimetics as anti-inflammatory agents are discussed.

The Role of Manganese Superoxide Dismutase in Skin Cancer

Recent studies have shown that antioxidant enzyme expression and activity are drastically reduced in most human skin diseases, leading to propagation of oxidative stress and continuous disease progression. However, antioxidants, an endogenous defense system against reactive oxygen species (ROS), can be induced by exogenous sources, resulting in protective effects against associated oxidative injury. Many studies have shown that the induction of antioxidants is an effective strategy to combat various disease states. In one approach, a SOD mimetic was applied topically to mouse skin in the two-stage skin carcinogenesis model. This method effectively reduced oxidative injury and proliferation without interfering with apoptosis. In another approach, Protandim, a combination of 5 well-studied medicinal plants, was given via dietary administration and significantly decreased tumor incidence and multiplicity by 33% and 57%, respectively. These studies suggest that alterations in antioxidant response may be a novel approach to chemoprevention. This paper focuses on how regulation of antioxidant expression and activity can be modulated in skin disease and the potential clinical implications of antioxidant-based therapies.

Oxidized Low-Density Lipoprotein-Activated c-Jun NH2-Terminal Kinase Regulates Manganese Superoxide Dismutase Ubiquitination

Oxidized low-density lipoprotein (oxLDL) modulates intracellular redox status and induces apoptosis in endothelial cells. However, the signal pathways and molecular mechanism remain unknown. In this study, we investigated the role of manganese superoxide dismutase (Mn-SOD) on oxLDL-induced apoptosis via c-Jun NH2-terminal kinase (JNK)-mediated ubiquitin/proteasome pathway. OxLDL induced JNK phosphorylation that peaked at 30 minutes in human aortic endothelial cells. Fluorescence-activated cell sorting analysis revealed that oxLDL increased mitochondrial superoxide production by 1.88+/-0.19-fold and mitochondrial membrane potential by 18%. JNK small interference RNA (siJNK) reduced oxLDL-induced mitochondrial superoxide production by 88.4% and mitochondrial membrane potential by 61.7%. OxLDL did not affect Mn-SOD mRNA expression, but it significantly reduced Mn-SOD protein level, which was restored by siJNK. Immunoprecipitation by ubiquitin antibody revealed that oxLDL increased ubiquitination of Mn-SOD, which was inhibited by siJNK. OxLDL-induced caspase-3 activities were also attenuated by siJNK but were enhanced by Mn-SOD small interfering RNA. Furthermore, overexpression of Mn-SOD abrogated oxLDL-induced caspase-3 activities. OxLDL-induced JNK activation regulates mitochondrial redox status and Mn-SOD protein degradation via JNK-dependent ubiquitination, leading to endothelial cell apoptosis.