Gene transfer of extracellular superoxide dismutase improves endothelial function in rats with heart failure

2005 ◽  
Vol 289 (2) ◽  
pp. H525-H532 ◽  
Author(s):  
Shinichiro Iida ◽  
Yi Chu ◽  
Joseph Francis ◽  
Robert M. Weiss ◽  
Carol A. Gunnett ◽  
...  
Keyword(s):  
Heart Failure ◽  
Superoxide Dismutase ◽  
Risk Factor ◽  
Endothelial Dysfunction ◽  
Gene Transfer ◽  
Endothelial Function ◽  
Mesenteric Artery ◽  
Extracellular Superoxide Dismutase ◽  
Protective Effects ◽  
Sod Activity

Oxidative stress is associated with endothelial dysfunction in heart failure. The goals of this study were to determine whether 1) gene transfer of extracellular superoxide dismutase (ecSOD) reduces levels of superoxide and improves endothelial function in the aorta and mesenteric artery in rats with heart failure, and 2) the heparin-binding domain (HBD) of ecSOD, by which ecSOD binds to cells, is required for protective effects of ecSOD. Seven weeks after coronary ligation, in rats with heart failure and sham-operated rats, we injected adenoviral vectors intravenously that express ecSOD, ecSOD with deletion of the HBD (ecSODΔHBD), or a control vector. Four days after injection of viruses, responses to acetylcholine, ADP, and sodium nitroprusside were examined in rings of the aorta and mesenteric artery. ecSOD bound to endothelium and increased SOD activity in the aorta after gene transfer of ecSOD, not ecSODΔHBD. Gene transfer of ecSOD, but not ecSODΔHBD, reduced levels of superoxide and improved relaxation to acetylcholine and ADP in the aorta and mesenteric artery from rats with heart failure. Improvement of relaxation to acetylcholine in the mesenteric artery from rats with heart failure after gene transfer of ecSOD was mediated in part by hydrogen peroxide. The major finding of this study is that the HBD of ecSOD is necessary for protection against endothelial dysfunction in rats with heart failure. We speculate that a common gene variant in the HBD of ecSOD, which is a risk factor for ischemic heart disease, may be a risk factor for vascular maladaptation and endothelial dysfunction in heart failure.

Vascular effects of a common gene variant of extracellular superoxide dismutase in heart failure

2006 ◽  
Vol 291 (2) ◽  
pp. H914-H920 ◽  
Author(s):  
Shinichiro Iida ◽  
Yi Chu ◽  
Robert M. Weiss ◽  
Yu Ming Kang ◽  
Frank M. Faraci ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Superoxide Dismutase ◽  
Gene Transfer ◽  
Coronary Artery Ligation ◽  
Extracellular Superoxide Dismutase ◽  
Gene Variant ◽  
Vascular Effects ◽  
Common Gene ◽  
Increased Risk

A common gene variant of human extracellular superoxide dismutase (ecSOD), in ∼5% of humans, is associated with increased risk of ischemic heart disease. The purpose of this study was to examine vascular effects of ecSOD with effects of the ecSOD variant (ecSODR213G) in rats with heart failure. Seven weeks after coronary artery ligation, we studied rats with heart failure and sham-operated rats. Adenoviral vectors expressing human ecSOD, ecSODR213G, or a control virus were injected intravenously. In the aorta from rats with heart failure, responses to acetylcholine (69 ± 4% relaxation, means ± SE) and basal levels of nitric oxide (NO) (vasoconstrictor responses to a NO synthase inhibitor) were greatly impaired, and levels of superoxide and peroxynitrite were increased. Gene transfer of ecSOD restored responses to acetylcholine (92 ± 2% relaxation) and basal levels of NO to normal and reduced levels of superoxide [from 2.3 ± 0.2 to 0.9 ± 0.2 relative light units per second per millimeter squared (RLU·s−1·mm−2)] and peroxynitrite (from 2.4 ± 0.2 to 0.9 ± 0.1 RLU·s−1·mm−2) in the aorta from rats with heart failure. Gene transfer of ecSODR213G produced little or no improvement. Responses to nitroprusside were not different among the groups. Expression of endogenous mRNA for SODs (CuZnSOD, MnSOD, and ecSOD) and endothelial NOS in the aorta was not different among the groups. In contrast to ecSOD, gene transfer of ecSODR213G in rats with heart failure has minimal beneficial effect on oxidative stress, endothelial function, or basal bioavailability of NO. We speculate that greatly diminished efficacy of ecSODR213G in protection against oxidative stress and endothelial dysfunction may contribute to increased risk of cardiovascular disease in humans with ecSODR213G.

scholarly journals Protective effect of extracellular superoxide dismutase on endothelial function during aging

2009 ◽  
Vol 296 (6) ◽  
pp. H1920-H1925 ◽  
Author(s):  
Donald D. Lund ◽  
Yi Chu ◽  
Jordan D. Miller ◽  
Donald D. Heistad
Keyword(s):  
Superoxide Dismutase ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Ex Vivo ◽  
Vascular Dysfunction ◽  
Extracellular Superoxide Dismutase ◽  
Mrna Levels ◽  
Wild Type ◽  
Vasomotor Function ◽  
Old Mice

Endothelial vasomotor function decreases with increasing age. Extracellular superoxide dismutase (ecSOD) protects against vascular dysfunction in several disease states. The purpose of this study was to determine whether endogenous ecSOD protects against endothelial dysfunction in old mice. Vasomotor function of the aorta was studied ex vivo in wild-type (ecSOD+/+) and ecSOD-deficient (ecSOD−/−) mice at 11 (adult) and 29 (old) mo of age. Maximal relaxation to acetylcholine (10−4 M) was impaired in vessels from adult ecSOD−/− mice [75 ± 3% (mean ± SE)] compared with wild-type mice (89 ± 2%, P < 0.05). Maximal relaxation to acetylcholine (10−4 M) was profoundly impaired in aorta from old ecSOD−/− mice (45 ± 5%) compared with wild-type mice (75 ± 4%, P < 0.05). There was a significant correlation between expression of ecSOD and maximal relaxation to acetylcholine in adult and old mice. Tempol (1 mM), a scavenger of superoxide, improved relaxation in response to acetylcholine (63 ± 8%) in old ecSOD−/− mice ( P < 0.05), but not wild-type mice (75 ± 4%). Maximal relaxation to sodium nitroprusside was similar in aorta from adult and old wild-type and ecSOD−/− mice. Quantitative RT-PCR showed a decrease in mRNA levels of ecSOD and catalase in aorta of old mice and an increase in levels of TNFα and Nox-4 in aorta of old mice compared with adult mice. The findings support the hypothesis that impaired antioxidant mechanisms may contribute to cumulative increases in oxidative stress and impaired endothelial function in old mice. In conclusion, endogenous ecSOD plays an important role in protection against endothelial dysfunction during aging.

scholarly journals Gene transfer of superoxide dismutase isoforms reverses endothelial dysfunction in diabetic rabbit aorta

2001 ◽  
Vol 280 (6) ◽  
pp. H2516-H2523 ◽  
Author(s):  
Michela Zanetti ◽  
Jun'Ichi Sato ◽  
Zvonimir S. Katusic ◽  
Timothy O'Brien
Keyword(s):  
Superoxide Dismutase ◽  
Endothelial Dysfunction ◽  
Gene Transfer ◽  
Manganese Superoxide Dismutase ◽  
Ex Vivo ◽  
Rabbit Aorta ◽  
Sod Activity ◽  
Manganese Superoxide ◽  
Diabetic Rabbit ◽  
Copper Zinc

Increased production of oxygen free radicals is an important mechanism of endothelial dysfunction in diabetes mellitus. Our goal was to test whether adenovirus (Ad)-mediated gene transfer of copper/zinc (CuZn) or manganese superoxide dismutase (Mn SOD) improves relaxation of diabetic vessels. The aortas from 9 alloxan-induced diabetic mellitus (DM) and 16 control rabbits were used. Control and DM rings were transduced ex vivo with Ad vectors encoding Mn SOD (AdMn SOD), CuZn SOD (AdCuZn SOD), β-galactosidase (Adβgal), or diluents. In the absence of gene transfer, SOD activity was significantly increased in DM aortas. Transgene expression in DM AdCuZn SOD and DM AdMn SOD-transduced vessels was confirmed by Western blot analysis and by increased SOD activity (DM AdCuZn SOD, 76.2 ± 9.3; DM AdMn SOD, 65.2 ± 4.8; P < 0.05 vs. DM Adβgal; 50.9 ± 4.4 U/mg protein). Superoxide production was increased in DM Adβgal-transduced aorta and relaxations to acetylcholine were impaired in these vessels. Gene transfer of CuZn SOD and Mn SOD corrected both of these defects. Thus Ad-mediated gene transfer CuZn and Mn SOD to the diabetic aorta improves endothelium-dependent relaxation.

Protective Effects of Ginsenosides on 17α-Ethynyelstradiol-Induced Intrahepatic Cholestasis via Anti-Oxidative and Anti-Inflammatory Mechanisms in Rats

2017 ◽  
Vol 45 (08) ◽  
pp. 1613-1629 ◽  
Author(s):  
Yan-Jiao Xu ◽  
Zao-Qin Yu ◽  
Cheng-Liang Zhang ◽  
Xi-Ping Li ◽  
Cheng-Yang Feng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alkaline Phosphatase ◽  
Superoxide Dismutase ◽  
Protein Expression ◽  
Intrahepatic Cholestasis ◽  
Serum Levels ◽  
Total Bile Acid ◽  
Protective Effects ◽  
Sod Activity ◽  
Mda Content

The present study was designed to assess the effects and potential mechanisms of ginsenosides on 17[Formula: see text]-ethynyelstradiol (EE)-induced intrahepatic cholestasis (IC). Ginsenoside at doses of 30, 100, 300[Formula: see text]mg/kg body weight was intragastrically (i.g.) given to rats for 5 days to examine the effect on EE-induced IC. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bile acid (TBA) were measured. Hepatic malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were determined. Protein expression of proinflammatory cytokines TNF-[Formula: see text], IL-6 and IL-1[Formula: see text] was analyzed by immunohistochemistry and Western blot. Results indicated that ginsenosides remarkably prevented EE-induced increase in the serum levels of AST, ALT, ALP and TBA. Moreover, the elevation of hepatic MDA content induced by EE was significantly reduced, while hepatic SOD activities were significantly increased when treated with ginsenosides. Histopathology of the liver tissue showed that pathological injuries were relieved after treatment with ginsenosides. In addition, treatment with ginsenosides could significantly downregulate the protein expression of TNF-[Formula: see text], IL-6 and IL-1[Formula: see text] compared with EE group. These findings indicate that ginsenosides exert the hepatoprotective effect on EE-induced intrahepatic cholestasis in rats, and this protection might be attributed to the attenuation of oxidative stress and inflammation.

scholarly journals The Impact of Fullerenes as Doxorubicin Nano-Transporters on Metallothionein and Superoxide Dismutase Status in MCF-10A Cells

Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 102
Author(s):  
Natalia Zaręba ◽  
Klaudia Więcławik ◽  
Rene Kizek ◽  
Bozena Hosnedlova ◽  
Marta Kepinska
Keyword(s):  
Superoxide Dismutase ◽  
Light Scattering ◽  
Control Sample ◽  
C60 Fullerene ◽  
Tetrazolium Salt ◽  
Protective Effects ◽  
Sod Activity ◽  
Healthy Human ◽  
Salt Reduction ◽  
The Impact

This study aimed to synthesise C60–DOX complexes followed by the analysis of their effect on the concentration of metallothionein (MT) as a non-enzymatic antioxidant and on the concentration and activity of superoxide dismutase (SOD) as an antioxidant enzyme in healthy human mammary MCF-10A cells. Dynamic light scattering and electrophoretic light scattering were used to establish the size and zeta potential of the complexes. The MT and SOD concentrations were determined using the ELISA method; SOD activity was determined by tetrazolium salt reduction inhibition. Lower MT concentration following exposure of cells to both DOX and C60 fullerene compared to the control sample was found. However, the concentration of this protein increased as a consequence of the C60–DOX complexes action on MCF-10A cells compared to the control. C60 used alone did not affect the concentration and activity of SOD in MCF-10A cells. Application of free DOX did not activate cellular antioxidant defence in the form of an increase in SOD concentration or its activity. In contrast treatment of cells with the C60–DOX complex resulted in a decrease in SOD1 concentration and a significant increase in SOD activity compared to cells treated with free DOX, C60 and control. Thus, it was found that C60–DOX complexes showed potential for protective effects against DOX-induced toxicity to MCF-10A cells.

scholarly journals Human extracellular superoxide dismutase is a tetramer composed of two disulphide-linked dimers: a simplified, high-yield purification of extracellular superoxide dismutase

1996 ◽  
Vol 317 (1) ◽  
pp. 51-57 ◽  
Author(s):  
Tim D. OURY ◽  
James D. CRAPO ◽  
Zuzana VALNICKOVA ◽  
Jan J. ENGHILD
Keyword(s):  
Superoxide Dismutase ◽  
Limited Proteolysis ◽  
Exchange Chromatography ◽  
Disulphide Bond ◽  
High Yield ◽  
Human Aorta ◽  
Extracellular Superoxide Dismutase ◽  
Heparin Binding ◽  
Sod Activity ◽  
Native Page

Studies examining the biochemical characteristics and pharmacological properties of extracellular superoxide dismutase (EC SOD) have been severely limited because of difficulties in purifying the enzyme. Recently EC SOD was found to exist in high concentrations in the arteries of most mammals examined and it is the predominant form of SOD activity in many arteries. We now describe a three-step, high-yield protocol for the purification of EC SOD from human aorta. In the first step, the high affinity of EC SOD for heparin is utilized to obtain a fraction in which EC SOD constitutes roughly 13% of the total protein compared with only 0.3% of that of the starting material. In addition, over 80% of the original EC SOD activity present in the aortic homogenate was retained after the first step of purification. EC SOD was further purified using a combination of cation- and anion-exchange chromatography. The overall yield of EC SOD from this purification procedure was 46%, with over 4 mg of EC SOD obtained from 230 g of aorta. Purified EC SOD was found to exist predominantly as a homotetramer composed of two disulphide-linked dimers. However, EC SOD was also found to form larger multimers when analysed by native PAGE. It was shown by urea denaturation that the formation of multimers increased the thermodynamic stability of the protein. Limited proteolysis of EC SOD suggested that there is one interchain disulphide bond covalently linking two subunits. This disulphide bond involves cysteine-219 and appears to link the heparin-binding domains of the two subunits.

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