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Induced expression of manganese superoxide dismutase by non-toxic concentrations of oxidized low-density lipoprotein (oxLDL) protects against oxLDL-mediated cytotoxicity.

ABSTRACT: Oxidized low-density lipoprotein (oxLDL) affects macrophages and plays a critical role in the development of atherosclerosis. In the present paper, we demonstrate that high concentrations of oxLDL provoked apoptosis of human Mono-Mac-6 cells, which was blocked by diphenylene-iodonium (DPI), an inhibitor of flavin-containing enzymes, such as NADPH oxidase, suggesting the involvement of reactive oxygen species (ROS). Importantly, pre-treatment of cells with low concentrations of oxLDL prevented apoptosis in response to high concentrations of oxLDL by up-regulating manganese superoxide dismutase (MnSOD). DPI prevented expression of MnSOD by oxLDL, whereas inhibitors of cytochrome P450 (methoxalen) or xanthine oxidase (allopurinol) did not, thus pointing to a role of NADPH-oxidase-derived ROS in oxLDL-induced MnSOD expression. Transfection of cells with MnSOD antisense, but not scrambled antisense, oligonucleotides significantly attenuated oxLDL-mediated MnSOD expression and hindered cytoprotective effects of non-toxic oxLDL concentrations. Our findings suggest that up-regulation of MnSOD by low concentrations of oxLDL is critical for protection towards oxLDL-mediated cytotoxicity.

SUBMITTER: Shatrov VA

PROVIDER: S-EPMC1223623 | biostudies-other | 2003 Sep

REPOSITORIES: biostudies-other

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Oxidized low-density lipoprotein-activated c-Jun NH2-terminal kinase regulates manganese superoxide dismutase ubiquitination: implication for mitochondrial redox status and apoptosis.

Project description: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.

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Project description:Manganese superoxide dismutase is an important antioxidant defense metalloenzyme that protects cells from damage by the toxic oxygen metabolite, superoxide free radical, formed as an unavoidable by-product of aerobic metabolism. Many years of research have gone into understanding how the metal cofactor interacts with small molecules in its catalytic role. In contrast, very little is presently known about how the protein acquires its metal cofactor, an important step in the maturation of the protein and one that is absolutely required for its biological function. Recent work is beginning to provide insight into the mechanisms of metal delivery to manganese superoxide dismutase in vivo and in vitro.

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The relationship of the lipoprotein SsaB, manganese and superoxide dismutase in Streptococcus sanguinis virulence for endocarditis.

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Six-coordinate manganese(3+) in catalysis by yeast manganese superoxide dismutase.

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Insights into Manganese Superoxide Dismutase and Human Diseases.

Project description:Redox equilibria and the modulation of redox signalling play crucial roles in physiological processes. Overproduction of reactive oxygen species (ROS) disrupts the body's antioxidant defence, compromising redox homeostasis and increasing oxidative stress, leading to the development of several diseases. Manganese superoxide dismutase (MnSOD) is a principal antioxidant enzyme that protects cells from oxidative damage by converting superoxide anion radicals to hydrogen peroxide and oxygen in mitochondria. Systematic studies have demonstrated that MnSOD plays an indispensable role in multiple diseases. This review focuses on preclinical evidence that describes the mechanisms of MnSOD in diseases accompanied with an imbalanced redox status, including fibrotic diseases, inflammation, diabetes, vascular diseases, neurodegenerative diseases, and cancer. The potential therapeutic effects of MnSOD activators and MnSOD mimetics are also discussed. Targeting this specific superoxide anion radical scavenger may be a clinically beneficial strategy, and understanding the therapeutic role of MnSOD may provide a positive insight into preventing and treating related diseases.

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Association of copper-zinc superoxide dismutase (SOD1) and manganese superoxide dismutase (SOD2) genes with nonsyndromic myelomeningocele.

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Switch of mitochondrial superoxide dismutase into a prooxidant peroxidase in manganese-deficient cells

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2017-12-05 | GSE106206 | GEO

human primary monocytes: Control vs. oxLDL(oxidized low density lipoprotein)-stimulated 6h vs oxLDL-stimulated 12h

Project description:total RNA profiling of human primary monocytes comparing control untreated oxLDL cells with oxLDL cells for different time (6h and 12h), The latter makes monocytes to macrophage and foam cells.

2009-04-03 | GSE15514 | GEO

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