scholarly journals Vasodilatory and vascular mitochondrial respiratory function with advancing age: evidence of a free radically mediated link in the human vasculature

2020 ◽  
Vol 318 (4) ◽  
pp. R701-R711 ◽  
Author(s):  
Soung Hun Park ◽  
Oh Sung Kwon ◽  
Song-Young Park ◽  
Joshua C. Weavil ◽  
Jay R. Hydren ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Free Radical ◽  
Respiratory Function ◽  
Respiratory Control ◽  
Free Radical Production ◽  
Radical Production ◽  
Age Related ◽  
Significant Difference ◽  
Vasodilatory Function ◽  
Mitochondrial Respiratory

Recognizing the age-related decline in skeletal muscle feed artery (SMFA) vasodilatory function, this study examined the link between vasodilatory and mitochondrial respiratory function in the human vasculature. Twenty-four SMFAs were harvested from young (35 ± 6 yr, n = 9) and old (71 ± 9 yr, n = 15) subjects. Vasodilation in SMFAs was assessed, by pressure myography, in response to flow-induced shear stress, acetylcholine (ACh), and sodium nitroprusside (SNP) while mitochondrial respiration was measured, by respirometry, in permeabilized SMFAs. Endothelium-dependent vasodilation was significantly attenuated in the old, induced by both flow (young: 92 ± 3, old: 45 ± 4%) and ACh (young: 92 ± 3, old: 54 ± 5%), with no significant difference in endothelium-independent vasodilation. Complex I and I + II state 3 respiration was significantly lower in the old (CI young: 10.1 ± 0.8, old: 7.0 ± 0.4 pmol·s−1·mg−1; CI + II young: 12.3 ± 0.6, old: 7.6 ± 0.4 pmol·s−1·mg−1). The respiratory control ratio (RCR) was also significantly attenuated in the old (young: 2.2 ± 0.1, old: 1.1 ± 0.1). Furthermore, state 3 (CI + II) and 4 respiration, as well as RCR, were significantly correlated ( r = 0.49–0.86) with endothelium-dependent, but not endothelium-independent, function. Finally, the direct intervention with mitochondrial-targeted antioxidant (MitoQ) significantly improved endothelium-dependent vasodilation in the old but not in the young. Thus, the age-related decline in vasodilatory function is linked to attenuated vascular mitochondrial respiratory function, likely by augmented free radicals. NEW & NOTEWORTHY In human skeletal muscle feed arteries, the well-recognized age-related fall in endothelium-dependent vasodilatory function is strongly linked to a concomitant fall in vascular mitochondrial respiratory function. The direct intervention with the mitochondrial-targeted antioxidant restored vasodilatory function in the old but not in the young, supporting the concept that exacerbated mitochondrial-derived free radical production is linked to age-related vasodilatory dysfunction. Age-related vasodilatory dysfunction in humans is linked to attenuated vascular mitochondrial respiratory function, likely a consequence of augmented free radical production.

Measurement of myocardial free radical production during exercise using EPR spectroscopy

2006 ◽  
Vol 290 (6) ◽  
pp. H2453-H2458 ◽  
Author(s):  
Jay H. Traverse ◽  
Yuri E. Nesmelov ◽  
Melanie Crampton ◽  
Paul Lindstrom ◽  
David D. Thomas ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Free Radical ◽  
Treadmill Exercise ◽  
Electron Paramagnetic Resonance Spectroscopy ◽  
Resonance Spectroscopy ◽  
Paramagnetic Resonance ◽  
Free Radical Production ◽  
Radical Production ◽  
Significant Difference ◽  
Carbon Centered Radical

Exercise is associated with an increase in oxygen flux through the mitochondrial electron transport chain that has recently been demonstrated to increase the production of reactive oxygen species (ROS) in skeletal muscle. This study examined whether exercise also causes free radical production in the heart. We measured ROS production in seven chronically instrumented dogs during rest and treadmill exercise (6.4 km/h at 10° grade; and heart rate, 204 ± 3 beats/min) using electron paramagnetic resonance spectroscopy in conjunction with the spin trap α-phenyl- tert-butylnitrone (PBN) (0.14 mol/l) in blood collected from the aorta and coronary sinus (CS). To improve signal detection, the free radical adducts were deoxygenated over a nitrogen stream for 15 min and extracted with toluene. The hyperfine splitting constants of the radicals were αN = 13.7 G and αH = 1.0 G, consistent with an alkoxyl or carbon-centered radical. Resting aortic and CS PBN adduct concentrations were 6.7 and 6.3 × 108 arbitrary units ( P = not significant). Both aortic and CS adduct concentrations increased during exercise, but there was no significant difference between the aortic and CS concentrations. Thus, in contrast to skeletal muscle, submaximal treadmill exercise did not result in detectable free radical production by the heart.

Phenyl N-Tert-Butylnitrone (PBN) Protects Syngeneic Marrow Transplant Recipients from the Lethal Cytokine Syndrome Occurring after Agonistic CD40 Antibody Administration.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2128-2128
Author(s):  
William R. Drobyski ◽  
Nadine Halligan ◽  
Richard Komorowski ◽  
Brent Logan ◽  
William J. Murphy ◽  
...  
Keyword(s):  
Free Radical ◽  
Organ Damage ◽  
Marrow Transplant ◽  
Antitumor Effects ◽  
Free Radical Production ◽  
Radical Production ◽  
Gut Toxicity ◽  
Significant Difference ◽  
Ifn Γ ◽  
Agonistic Cd40 Antibody

Abstract Administration of agonistic monoclonal antibodies or recombinant cytokines is a potential approach to enhance antitumor immunity in bone marrow transplant (BMT) recipients, but is complicated by toxicity due to proinflammatory cytokine-mediated vital organ damage. Inflammatory cytokines are known to induce free radical production which we hypothesized might be the proximate cause of toxicity in this setting. Phenyl-tert-butylnitrone (PBN) is a spin trap inhibitor, that has been used in electron paramagnetic resonance (EPR) studies to trap free radicals so they can be visualized by EPR spectroscopy. To test whether PBN could mitigate cytokine-mediated organ damage, we employed a murine syngeneic transplant model in which administration of agonistic CD40 antibody to mice early post BMT results in lethality due to production of high levels of cytokines such as IL-12 and IFN-γ, leading to fatal gut toxicity. Lethally irradiated C57BL/6J (B6) mice were transplanted with B6 BM and then treated with either IgG or anti-CD40 antibody (7 μg) on days 1–4 post-BMT. Cohorts of anti-CD40-antibody-treated mice were then administered either DMSO or PBN (50 mg/kg BID) on days 0–5 post-BMT. Administration of PBN completely protected BMT recipients from anti-CD40 antibody-induced mortality (0% survival CD40/DMSO versus 100% survival CD40/PBN). This was attributable to a significant reduction in gut toxicity as determined using a pathological scoring system. To examine the mechanism by which mice were protected, cytokine and nitrate/nitrite levels were measured to determine whether PBN inhibited production of proinflammatory mediators. Administration of anti-CD40 antibody resulted in a significant increase in IL-12, IFN-γ,TNF-α, and nitrate/nitrite levels compared to IgG/PBN-treated control mice. However, there was no significant difference in serum measurements of these cytokines in CD40/PBN compared to CD40/DMSO-treated animals. These data demonstrated that the protective effects of PBN were not attributable to a reduction in cytokine mediators and suggested that the action of PBN occurred downstream of these inflammatory cytokine signaling pathways, through inhibition of free radical production. Cytokines, such as IL-12 and IFN-γ, are also important downstream mediators of the antitumor effects induced by agonistic CD40 antibody. Therefore to directly test whether PBN compromised these antitumor effects, B6 mice were intravenously administered 107 EL4 cells and then treated on days 3-6 with either rat IgG or anti-CD40 antibody. Since EL4 cells do not express CD40, tumor regression mediated by anti-CD40 antibody is attributable to augmentation of host immunity and has been shown to dependent upon IFN-γ. B6 mice were challenged with a lethal dose EL4 tumor cells and then treated with IgG or agonistic CD40 antibody (500 μg/day) in the presence or absence of PBN. IgG-treated control mice all died within 20 days. In contrast, CD40/DMSO and CD40/PBN-treated mice all survived >80 days after tumor challenge indicating that PBN did not compromise antitumor effects. We conclude that PBN administration may represent a novel approach for reduction of toxicity without compromise of antitumor effects resulting from administration of therapeutic antibodies in BMT recipients.

scholarly journals Peroxisomes and free radical production: cell aging

2014 ◽  
Vol 2 (3) ◽  
Author(s):  
Manuel Sánchez-Gutiérez ◽  
Nancy Vargas-Mendoza ◽  
Jeannett A. Izquierdo-Vega ◽  
Eduardo O. Madrigal Santillán
Keyword(s):  
Oxidative Stress ◽  
Cardiovascular Disease ◽  
Free Radical ◽  
Eukaryotic Cells ◽  
Cell Aging ◽  
Free Radical Production ◽  
Radical Production ◽  
Age Related ◽  
Production Cell ◽  
Cellular Organelles

Peroxisomes are cellular organelles present in the eukaryotic cells that are responsible for detoxification processes such as oxidation of fatty acids, biosynthesis of glycerolipids and isoprenoids, among others. Due to the number of functions which they carry out, they are conditioned to an elevated production of free radicals (FR), for which they have a sophisticated antioxidant system consisting of enzymes that can neutralize free radical molecules. The importance of peroxisomes in the development of age-related diseases such as diabetes, cancer and cardiovascular disease has been reported recently. In this paper, we review briefly these organelles, treating aspects such as their evolution, functions and the role they play in oxidative stress processes associated with aging.

Chemiluminescence as an index of drug-induced free radical production in pancreatic islets

Diabetes ◽  
1984 ◽  
Vol 33 (2) ◽  
pp. 160-163 ◽  
Author(s):  
K. Asayama ◽  
D. English ◽  
A. E. Slonim ◽  
I. M. Burr
Keyword(s):  
Free Radical ◽  
Pancreatic Islets ◽  
Drug Induced ◽  
Free Radical Production ◽  
Radical Production

Features of the oxidative status in patients with lupus nephritis

2020 ◽  
Vol 24 (1) ◽  
pp. 39-44
Author(s):  
E. V. Smirnova ◽  
E. V. Proskurnina ◽  
T. N. Krasnova
Keyword(s):  
Oxidative Stress ◽  
Free Radical ◽  
Lupus Nephritis ◽  
Blood Plasma ◽  
Respiratory Burst ◽  
Oxidative Status ◽  
Free Radical Production ◽  
Radical Production ◽  
Neutrophil Activity ◽  
Kidney Involvement

BACKGROUND. Oxidative status impairment plays a significant role in the pathogenesis of SLE and lupus nephritis (LN). The data about oxidative status in this disease are incomplete, that’s why it’s necessary to use a new approach to study it. THE AIM: To study oxidative status in SLE patients with kidney involvement. PATIENTS AND METHODS:53 patients with SLE were included in this prospective study, among them 40 patients with different severity of kidney involvement, control group were 87 healthy donors. Oxidative stress parameters were measured: antioxidant activity (AOA) of blood plasma and parameters, characterizing the state of the main source of reactive oxygen species (ROS) – neutrophils, more specifically: specific spontaneous neutrophil activity, specific stimulated activity (peak and integral), coefficient of respiratory burst attenuation, representing the rate of free radical production decrease after stimulation, the higher the value of this parameter, the slower is free radical production decrease. RESULTS. It was shown elevation of neutrophil free radical-producing activity parameters and elevation of blood plasma AOA in patients with LN, comparing to healthy controls. Immunosuppressive therapy with glucocorticosteroids (GCS) and cytostatics (CS) increased blood plasma AOA comparing to monotherapy with GCS. A correlation between oxidative status impairment and intensity of inflammatory reactions was found: correlation of respiratory burst attenuation coefficient with blood sedimentation rate was shown. Reduction of spontaneous free radical-producing neutrophil activity was found in LN patients with NS, which might be the result of neutrophil functional activity attenuation in high disease activity. CONCLUSION. The increased free radical-producing neutrophil activity was shown, which might be the cause of oxidative stress in SLE with LN. It seems warranted investigation of these parameters in samples of larger volume to search targets aimed at neutrophils. The necessity of antioxidant therapy in patients with SLE seems doubtful, as they show significant increase of blood plasma AOA, which might result from compensatory reaction of human organism to oxidative stress and therapy with GCS and CS.

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