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.

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.

scholarly journals Role of oxidative stress and AT1 receptors in cerebral vascular dysfunction with aging

2009 ◽  
Vol 296 (6) ◽  
pp. H1914-H1919 ◽  
Author(s):  
Mary L. Modrick ◽  
Sean P. Didion ◽  
Curt D. Sigmund ◽  
Frank M. Faraci
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Vascular Dysfunction ◽  
Ang Ii ◽  
Wild Type ◽  
Very Old ◽  
Vascular Responses ◽  
Basilar Arteries ◽  
Old Mice ◽  
Cerebral Vascular

Vascular dysfunction occurs with aging. We hypothesized that oxidative stress and ANG II [acting via ANG II type 1 (AT1) receptors] promotes cerebral vascular dysfunction with aging. We studied young (5–6 mo), old (17–19 mo), and very old (23 ± 1 mo) mice. In basilar arteries in vitro, acetylcholine (an endothelium-dependent agonist) produced dilation in young wild-type mice that was reduced by ∼60 and 90% ( P < 0.05) in old and very old mice, respectively. Similar effects were seen using A23187, a second endothelium-dependent agonist. The vascular response to acetylcholine in very old mice was almost completely restored with tempol (a scavenger of superoxide) and partly restored by PJ34, an inhibitor of poly(ADP-ribose) polymerase (PARP). We used mice deficient in Mn-SOD (Mn-SOD+/−) to test whether this form of SOD protected during aging but found that age-induced endothelial dysfunction was not altered by Mn-SOD deficiency. Cerebral vascular responses were similar in young mice lacking AT1 receptors (AT1−/−) and wild-type mice. Vascular responses to acetylcholine and A23187 were reduced by ∼50% in old wild-type mice ( P < 0.05) but were normal in old AT1-deficient mice. Thus, aging produces marked endothelial dysfunction in the cerebral artery that is mediated by ROS, may involve the activation of PARP, but was not enhanced by Mn-SOD deficiency. Our findings suggest a novel and fundamental role for ANG II and AT1 receptors in age-induced vascular dysfunction.

scholarly journals Endothelial Function in a Mouse Model of Myeloperoxidase Deficiency

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Veronika Golubinskaya ◽  
Ulla Brandt-Eliasson ◽  
Li-Ming Gan ◽  
Martin Kjerrulf ◽  
Holger Nilsson
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Carotid Arteries ◽  
Contractile Force ◽  
Wild Type ◽  
High Potassium ◽  
High Concentrations ◽  
Old Mice ◽  
Deficient Mice ◽  
Lps Treatment

Myeloperoxidase (MPO) activity is suggested to reduce the function of vascular nitric oxide, thereby contributing to endothelial dysfunction, although data in rodents are inconclusive. We examined vascular contractile and relaxant responses in MPO-deficient (MPO-/-) and wild-type mice to investigate the role for myeloperoxidase in the development of endothelial dysfunction. Carotid and saphenous arteries were taken from 8-month-old mice and studied in a myograph. Responses of carotid arteries to phenylephrine, high potassium, or acetylcholine (Ach) were statistically not different from controls. Treatment with lipopolysaccharide (LPS; to enhance endothelial dysfunction) reduced responses to Ach inMPO-/-but did not affect responses in wild-type. In response to high concentrations of Ach, carotid arteries responded with transient contractions, which were not different between the groups and not affected by LPS treatment. Saphenous arteries fromMPO-/-had smaller normalized diameters and developed less contractile force. Vessels fromMPO-/-were less sensitive to Ach than controls. These data suggest that mature MPO-deficient mice do not show enhanced endothelial function compared to wild-type mice, even when provoked with LPS treatment. The EDHF response appears to be reduced in MPO deficiency.

Abstract 665: Activation of Histone Deacetylase 2: A Novel Strategy for Reversing Vascular Dysfunction in Atherogenesis

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Deepesh Pandey ◽  
Gautam Sikka ◽  
Yehudis Bergman ◽  
Jae H Kim ◽  
Sungwoo Ryoo ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Cell Activation ◽  
Vascular Dysfunction ◽  
Hdac Inhibitors ◽  
Ros Production ◽  
Promoter Regions ◽  
Endothelial Cell Activation ◽  
Novel Therapy ◽  
Histone Deacetylase 2

Arginase 2 is a critical target in atherosclerosis as it regulates both endothelial NO, fibrosis and inflammation. The increase in Arg2 activity with endothelial cell activation is dependent on both early post-translational dependent mechanisms as well as a later increase in Arg 2 expression. The regulators of Arg2 transcription in the endothelium have not been characterized. The goal of current study is to determine the role of specific HDACs in the regulation of endothelial Arg2 transcription and thereby endothelial function. The global HDAC inhibitor, trichostatin (TSA) both time and concentration-dependently increased Arg2 mRNA, protein levels and activity in both HAECs and mouse aortic rings, a process that leads to Arg2-dependent endothelial dysfunction. TSA and atherogenic stimulus enhances activity of common promoter regions of Arg 2. All non-selective Class I HDAC inhibitors (TSA, Scriptaid, varinostat) enhanced Arg2 expression, while only the, the HDCA 1 and 2 selective inhibitor, mocetinostat (MGCD) enhances Arg2 expression. Overexpression of HDAC 2, 3 or 8 in HAECs have no effect on Arg 2 expression while HDAC2 cDNA overexpression concentration-dependently suppresses Arg2 expression. Conversely, siRNA knockdown of HDAC2 enhances Arg2 expression. Additionally like TSA, mouse aortic rings pre-incubated with MGCD resulted in endothelial dysfunction. Finally HDAC inhibition with TSA decreased endothelial NO and increased ROS production in an arginase-inhibitable manner. In conclusion, HDAC2 is critical regulator of Arg2 expression thereby regulating endothelial NO and ROS production, and consequently endothelial function. Overexpression or activation of HDAC2 thus represents a novel therapy for the prevention and treatment of endothelial dysfunction and atherosclerosis.

CD14+CD16++ “nonclassical” monocytes are associated with endothelial dysfunction in patients with coronary artery disease

2017 ◽  
Vol 117 (05) ◽  
pp. 971-980 ◽  
Author(s):  
Karol Urbanski ◽  
Dominik Ludew ◽  
Grzegorz Filip ◽  
Magdalena Filip ◽  
Agnieszka Sagan ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Mononuclear Cells ◽  
Vascular Dysfunction ◽  
Activation Markers ◽  
Mammary Arteries ◽  
No Bioavailability ◽  
Artery Disease

SummaryEndothelial dysfunction and inflammation are key mechanisms of vascular disease. We hypothesised that heterogeneity of monocyte subpopulations may be related to the development of vascular dysfunction in coronary artery disease (CAD). Therefore, we examined the relationships between monocyte subsets (CD14++CD16– “classical – Mon1”, CD14++CD16+ “intermediate – Mon2” and CD14+CD16++ “nonclassical – Mon3”), endothelial function and risk factor profiles in 130 patients with CAD undergoing coronary artery bypass grafting. This allowed for direct nitric oxide (NO) bioavailability assessment using isometric tension studies ex vivo (acetylcholine; ACh- and sodium- nitropruside; SNP-dependent) in segments of internal mammary arteries. The expression of CD14 and CD16 antigens and activation markers were determined in peripheral blood mononuclear cells using flow cytometry. Patients with high CD14+CD16++ “nonclassical” and low CD14++CD16- “classical” monocytes presented impaired endothelial function. High frequency of CD14+CD16++ “nonclassical” monocytes was associated with increased vascular superoxide production. Furthermore, endothelial dysfunction was associated with higher expression of activation marker CD11c selectively on CD14+CD16++ monocytes. Nonclassical and classical monocyte frequencies remained independent predictors of endothelial dysfunction when major risk factors for atherosclerosis were taken into account (β =0.18 p=0.04 and β =-0.19 p=0.03, respectively). In summary, our data indicate that CD14+CD16++ “nonclassical” monocytes are associated with more advanced vascular dysfunction measured as NO-bioavailability and vascular reactive oxygen species production.

Differential effects of obesity on visceral vs. subcutaneous adipose arteries: role of shear activated Kir2.1 and alterations to the glycocalyx

2021 ◽  
Author(s):  
Sang Joon Ahn ◽  
Elizabeth Le Master ◽  
James C. Lee ◽  
Shane A. Phillips ◽  
Irena Levitan ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Ex Vivo ◽  
Flow Chamber ◽  
Dominant Negative ◽  
Obese Mice ◽  
Shear Sensitivity ◽  
Electrophysiological Recordings ◽  
Subcutaneous Adipose

Obesity imposes well-established deficits to endothelial function. We recently showed that obesity-induced endothelial dysfunction was mediated by disruption of the glycocalyx and a loss of Kir channel flow-sensitivity. However, obesity-induced endothelial dysfunction is not observed in all vascular beds: visceral adipose arteries (VAA), but not subcutaneous adipose arteries (SAA), exhibit endothelial dysfunction. Aim: To determine if differences in SAA vs. VAA endothelial function observed in obesity are attributed to differential impairment of Kir channels and alterations to the glycocalyx. Methods: Mice were fed a normal rodent diet, or a high fat Western diet to induce obesity. Flow-induced vasodilation (FIV) was measured ex vivo. Functional downregulation of endothelial Kir2.1 was accomplished by transducing adipose arteries from mice and obese humans with adenovirus containing a dominant-negative Kir2.1 construct. Kir function was tested in freshly isolated endothelial cells seeded in a flow chamber for electrophysiological recordings under fluid shear. Atomic force microscopy was used to assess biophysical properties of the glycocalyx. Results: Endothelial dysfunction was observed in VAA of obese mice and humans. Downregulating Kir2.1 blunted FIV in SAA, but had no effect on VAA, from obese mice and humans. Obesity abolished Kir shear-sensitivity in VAA endothelial cells and significantly altered the VAA glycocalyx. In contrast, Kir shear-sensitivity was observed in SAA endothelial cells from obese mice and effects on SAA glycocalyx were less pronounced. Conclusions: We reveal distinct differences in Kir function and alterations to the glycocalyx that we propose contribute to the dichotomy in SAA vs. VAA endothelial function with obesity.

scholarly journals The NRF2 knockout rat: a new animal model to study endothelial dysfunction, oxidant stress, and microvascular rarefaction

2016 ◽  
Vol 310 (4) ◽  
pp. H478-H487 ◽  
Author(s):  
Jessica R. C. Priestley ◽  
Katie E. Kautenburg ◽  
Marc C. Casati ◽  
Bradley T. Endres ◽  
Aron M. Geurts ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Endothelial Dysfunction ◽  
Oxidant Stress ◽  
Antioxidant Defenses ◽  
Start Codon ◽  
Heme Oxygenase 1 ◽  
Ang Ii ◽  
Wild Type ◽  
Transcription Activator ◽  
Therapeutic Benefits

Nuclear factor (erythroid-derived 2)-like-2 (NRF2) is a master antioxidant and cell protective transcription factor that upregulates antioxidant defenses. In this study we developed a strain of Nrf2 null mutant rats to evaluate the role of reduced NRF2-regulated antioxidant defenses in contributing to endothelial dysfunction and impaired angiogenic responses during salt-induced ANG II suppression. Nrf2−/− mutant rats were developed using transcription activator-like effector nuclease technology in the Sprague-Dawley genetic background, and exhibited a 41-bp deletion that included the start codon for Nrf2 and an absence of immunohistochemically detectable NRF2 protein. Expression of mRNA for the NRF2-regulated indicator enzymes heme oxygenase-1, catalase, superoxide dismutase 1, superoxide dismutase 2, and glutathione reductase was significantly lower in livers of Nrf2−/− mutant rats fed high salt (HS; 4% NaCl) for 2 wk compared with wild-type controls. Endothelium-dependent dilation to acetylcholine was similar in isolated middle cerebral arteries (MCA) of Nrf2−/− mutant rats and wild-type littermates fed low-salt (0.4% NaCl) diet, and was eliminated by short-term (3 days) HS diet in both strains. Low-dose ANG II infusion (100 ng/kg sc) reversed salt-induced endothelial dysfunction in MCA and prevented microvessel rarefaction in wild-type rats fed HS diet, but not in Nrf2−/− mutant rats. The results of this study indicate that suppression of NRF2 antioxidant defenses plays an essential role in the development of salt-induced oxidant stress, endothelial dysfunction, and microvessel rarefaction in normotensive rats and emphasize the potential therapeutic benefits of directly upregulating NRF2-mediated antioxidant defenses to ameliorate vascular oxidant stress in humans.

Role of extracellular superoxide dismutase in bleomycin-induced pulmonary fibrosis

2002 ◽  
Vol 282 (4) ◽  
pp. L719-L726 ◽  
Author(s):  
Russell P. Bowler ◽  
Mike Nicks ◽  
Karrie Warnick ◽  
James D. Crapo
Keyword(s):  
Oxidative Stress ◽  
Superoxide Dismutase ◽  
Pulmonary Fibrosis ◽  
Lung Injury ◽  
Immunohistochemical Staining ◽  
Extracellular Superoxide Dismutase ◽  
Wild Type ◽  
Injured Lung ◽  
Intracellular Oxidative Stress

Bleomycin administration results in well-described intracellular oxidative stress that can lead to pulmonary fibrosis. The role of alveolar interstitial antioxidants in this model is unknown. Extracellular superoxide dismutase (EC-SOD) is the primary endogenous extracellular antioxidant enzyme and is abundant in the lung. We hypothesized that EC-SOD plays an important role in attenuating bleomycin-induced lung injury. Two weeks after intratracheal bleomycin administration, we found that wild-type mice induced a 106 ± 25% increase in lung EC-SOD. Immunohistochemical staining revealed that a large increase in EC-SOD occurred in injured lung. Using mice that overexpress EC-SOD specifically in the lung, we found a 53 ± 14% reduction in bleomycin-induced lung injury assessed histologically and a 17 ± 6% reduction in lung collagen content 2 wk after bleomycin administration. We conclude that EC-SOD plays an important role in reducing the magnitude of lung injury from extracellular free radicals after bleomycin administration.

Sign in / Sign up

Export Citation Format

Share Document