scholarly journals Aging impairs flow-induced dilation in coronary arterioles: role of NO and H2O2

2009 ◽  
Vol 297 (3) ◽  
pp. H1087-H1095 ◽  
Author(s):  
Lori S. Kang ◽  
Rafael A. Reyes ◽  
Judy M. Muller-Delp
Keyword(s):  
Superoxide Dismutase ◽  
Hydroxyl Radical ◽  
Immunoblot Analysis ◽  
Radical Formation ◽  
Beneficial Effects ◽  
Protein Levels ◽  
Age Related ◽  
Old Rats ◽  
Coronary Arterioles ◽  
Reduced Flow

Aging contributes significantly to the development of cardiovascular disease and is associated with elevated production of reactive oxygen species (ROS). The beneficial effects of nitric oxide (NO)-mediated vasodilation are quickly abolished in the presence of ROS, and this effect may be augmented with aging. We previously demonstrated an age-induced impairment of flow-induced dilation in rat coronary arterioles. Therefore, the purpose of this study was to determine the effects of O2− scavenging, as well as removal of H2O2, the byproduct of O2− scavenging, on flow-mediated dilation in coronary resistance arterioles of young (4 mo) and old (24 mo) male Fischer 344 rats. Flow increased NO and H2O2 production as evidenced by enhanced diaminofluorescein and dichlorodihydrofluorescein fluorescence, respectively, whereas aging reduced flow-induced NO and H2O2 production. Endothelium-dependent vasodilation was evaluated by increasing intraluminal flow (5–60 nl/s) before and after treatment with the superoxide dismutase mimetic Tempol (100 μM), the H2O2 scavenger catalase (100 U/ml), or Tempol plus catalase. Catalase reduced flow-induced dilation in both groups, whereas Tempol and Tempol plus catalase diminished vasodilation in young but not old rats. Tempol plus deferoxamine (100 μM), an inhibitor of hydroxyl radical formation, reversed Tempol-mediated impairment of flow-induced vasodilation in young rats and improved flow-induced vasodilation in old rats compared with control. Immunoblot analysis revealed increases in endogenous superoxide dismutase, catalase, and nitrotyrosine protein levels with aging. Collectively, these data indicate that NO- and H2O2-mediated flow-induced signaling decline with age in coronary arterioles and that elevated hydroxyl radical formation contributes to the age-related impairment of flow-induced vasodilation.

scholarly journals Superoxide dismutase enhances the formation of hydroxyl radicals in the reaction of 3-hydroxyanthranilic acid with molecular oxygen

1988 ◽  
Vol 251 (3) ◽  
pp. 893-899 ◽  
Author(s):  
H Iwahashi ◽  
T Ishii ◽  
R Sugata ◽  
R Kido
Keyword(s):  
Hydrogen Peroxide ◽  
Superoxide Dismutase ◽  
Hydroxyl Radical ◽  
Molecular Oxygen ◽  
Hydroxyl Radicals ◽  
Fenton Reaction ◽  
Potassium Phosphate ◽  
Radical Formation ◽  
Superoxide Anions ◽  
Hydroxyanthranilic Acid

Superoxide dismutase (SOD) enhanced the formation of hydroxyl radicals, which were detected by using the e.s.r. spin-trapping technique, in a reaction mixture containing 3-hydroxyanthranilic acid (or p-aminophenol), Fe3+ ions, EDTA and potassium phosphate buffer, pH 7.4. The hydroxyl-radical formation enhanced by SOD was inhibited by catalase and desferrioxamine, and stimulated by EDTA and diethylenetriaminepenta-acetic acid, suggesting that both hydrogen peroxide and iron ions participate in the reaction. The hydroxyl-radical formation enhanced by SOD may be considered to proceed via the following steps. First, 3-hydroxyanthranilic acid is spontaneously auto-oxidized in a process that requires molecular oxygen and yields superoxide anions and anthranilyl radicals. This reaction seems to be reversible. Secondly, the superoxide anions formed in the first step are dismuted by SOD to generate hydrogen peroxide and molecular oxygen, and hence the equilibrium in the first step is displaced in favour of the formation of superoxide anions. Thirdly, hydroxyl radicals are generated from hydrogen peroxide through the Fenton reaction. In this Fenton reaction Fe2+ ions are available since Fe3+ ions are readily reduced by 3-hydroxyanthranilic acid. The superoxide anions do not seem to participate in the reduction of Fe3+ ions, since superoxide anions are rapidly dismuted by SOD present in the reaction mixture.

scholarly journals Maternal Resveratrol Supplementation Prevents Cognitive Decline in Senescent Mice Offspring

2019 ◽  
Vol 20 (5) ◽  
pp. 1134 ◽  
Author(s):  
Vanesa Izquierdo ◽  
Verónica Palomera-Ávalos ◽  
Sergio López-Ruiz ◽  
Anna-Maria Canudas ◽  
Mercè Pallàs ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cognitive Decline ◽  
Target Genes ◽  
Epigenetic Inheritance ◽  
Mtor Inhibition ◽  
Beneficial Effects ◽  
Protein Levels ◽  
Age Related ◽  
F2 Generation ◽  
Age Related Cognitive Decline

A variety of environmental factors contribute significantly to age-related cognitive decline and memory impairment in Alzheimer’s Disease (AD) and other neurodegenerative diseases. Nutrition can alter epigenetics, improving health outcomes, which can be transmitted across generations; this process is called epigenetic inheritance. We investigate the beneficial effects of maternal resveratrol supplementation in the direct exposed F1 generation and the transgenerational F2 generation. The offspring was generated from females Senescence Accelerated Mouse-Prone (SAMP8) fed a resveratrol-enriched diet for two months prior to mating. Object novel recognition and Morris Water Maze (MWM) demonstrated improvements in cognition in the 6-month-old F1 and F2 generations from resveratrol fed mothers. A significant increase in global DNA methylation with a decrease in hydroxymethylation in F1 and F2 were found. Accordingly, Dnmt3a/b and Tet2 gene expression changed. Methylation levels of Nrf2 and NF-kβ genes promoters raised in offspring, inducing changes in target genes expression, as well as hydrogen peroxide levels. Offspring that resulted from a resveratrol fed mother showed increase AMPKα activation, mTOR inhibition, and an increase in Pgc-1α gene expression and Beclin-1 protein levels. Endoplasmic reticulum stress sensors were found changed both in F1 and F2 generations. Overall, our results demonstrated that maternal resveratrol supplementation could prevent cognitive impairment in the SAMP8 mice offspring through epigenetic changes and cell signaling pathways.

scholarly journals Age impairs Flk-1 signaling and NO-mediated vasodilation in coronary arterioles

2008 ◽  
Vol 295 (6) ◽  
pp. H2280-H2288 ◽  
Author(s):  
Amanda J. LeBlanc ◽  
Robert D. Shipley ◽  
Lori S. Kang ◽  
Judy M. Muller-Delp
Keyword(s):  
Nitric Oxide ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Vascular Endothelial ◽  
Coronary Resistance ◽  
Young Rats ◽  
Age Related ◽  
Old Rats ◽  
Endothelial Growth Factor ◽  
Coronary Arterioles

Impairment of flow-induced vasodilation in coronary resistance arterioles may contribute to the decline in coronary vasodilatory reserve that occurs with advancing age. This study investigated the effects of age on flow-induced signaling and activation of nitric oxide (NO)-mediated vasodilation in coronary resistance arterioles. Coronary arterioles were isolated from young (∼6 mo) and old (∼24 mo) male Fischer-344 rats to assess vasodilation to flow, vascular endothelial growth factor (VEGF), and ACh. Flow- and VEGF-induced vasodilation of coronary arterioles was impaired with age ( P ≤ 0.05); however, ACh-induced vasodilation was preserved with age. NG-nitro-l-arginine methyl ester (l-NAME) (1 × 10−5 M) eliminated vasodilation to flow, VEGF, and ACh, indicating dependence of these responses on NO. SU-1498, an inhibitor of vascular endothelial growth factor receptor 2 (VEGFR, also known as Flk-1), abolished age-related differences in flow-induced vasodilation. Flow-stimulated phosphorylation of Flk-1 in coronary arterioles from young but not old rats and Flk-1 protein was reduced in coronary arterioles from old rats compared with those from young rats. Flow stimulated phosphorylation of endothelial nitric oxide synthase (eNOS) in coronary arterioles from both young and old rats. VEGF induced phosphorylation of both protein kinase B (Akt) and eNOS in coronary arterioles. VEGF-induced phosphorylation of Akt, but not eNOS, was significantly reduced in arterioles from old rats compared with arterioles from young rats. Wortmannin, an inhibitor of phosphatidylinositol (PI) 3-kinase, eliminated age-related differences in both flow- and VEGF-induced vasodilation. These results indicate that impairment of Flk-1/PI3-kinase signaling contributes to the reduction of flow-induced vasodilation in coronary arterioles with advancing age.

scholarly journals Age-Associated Changes in Antioxidants and Redox Proteins of Rat Heart

2019 ◽  
pp. 883-892
Author(s):  
P. Kaplán ◽  
Z. Tatarková ◽  
L. Lichardusová ◽  
M. Kmeťová Sivoňová ◽  
A. Tomašcová ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Protein Modification ◽  
Redox Regulation ◽  
Thioredoxin Reductase ◽  
Redox Balance ◽  
Regulatory Systems ◽  
Age Related ◽  
Uniform Array ◽  
Old Rats ◽  
Posttranslational Protein Modification

Oxidative stress and decline in cellular redox regulation have been hypothesized to play a key role in cardiovascular aging; however, data on antioxidant and redox regulating systems in the aging heart are controversial. The aim of the present study was to examine the effect of aging on critical antioxidant enzymes and two major redox-regulatory systems glutathione (GSH) and thioredoxin (Trx) system in hearts from adult (6-month-old), old (15-month-old), and senescent (26-month-old) rats. Aging was associated with a non-uniform array of changes, including decline in contents of reduced GSH and total mercaptans in the senescent heart. The activities of Mn-superoxide dismutase (SOD2), glutathione peroxidase (GPx), glutathione reductase (GR), and thioredoxin reductase (TrxR) exhibited an age-related decline, whereas catalase was unchanged and Cu,Zn-superoxide dismutase (SOD1) displayed only slight decrease in old heart and was unchanged in the senescent heart. GR, Trx, and peroxiredoxin levels were significantly reduced in old and/or senescent hearts, indicating a diminished expression of these proteins. In contrast, SOD2 level was unchanged in the old heart and was slightly elevated in the senescent heart. Decline in GPx activity was accompanied by a loss of GPx level only in old rats, the level in senescent heart was unchanged. These results indicate age-related posttranslational protein modification of SOD2 and GPx. In summary, our data suggest that changes are more pronounced in senescent than in old rat hearts and support the view that aging is associated with disturbed redox balance that could alter cellular signaling and regulation.

scholarly journals Age-Related Memory Impairment Is Associated with Increased zif268 Protein Accumulation and Decreased Rpt6 Phosphorylation

2020 ◽  
Vol 21 (15) ◽  
pp. 5352
Author(s):  
Sydney Trask ◽  
Brooke N. Dulka ◽  
Fred J. Helmstetter
Keyword(s):  
Cognitive Decline ◽  
Brain Regions ◽  
Regulatory Subunit ◽  
Protein Accumulation ◽  
Memory Retention ◽  
Protein Levels ◽  
Trace Fear Conditioning ◽  
Age Related ◽  
Old Rats ◽  
Trace Fear

Aging is associated with cognitive decline, including impairments in the ability to accurately form and recall memories. Some behavioral and brain changes associated with aging are evident as early as middle age, making the understanding of associated neurobiological mechanisms essential to aid in efforts aimed at slowing cognitive decline throughout the lifespan. Here, we found that both 15-month-old and 22-month-old rats showed impaired memory recall following trace fear conditioning. This behavioral deficit was accompanied by increased zif268 protein accumulation relative to 3-month-old animals in the medial prefrontal cortex, the dorsal and ventral hippocampi, the anterior and posterior retrosplenial cortices, the lateral amygdala, and the ventrolateral periaqueductal gray. Elevated zif268 protein levels corresponded with decreases in phosphorylation of the Rpt6 proteasome regulatory subunit, which is indicative of decreased engagement of activity-driven protein degradation. Together, these results identify several brain regions differentially impacted by aging and suggest that the accumulation of proteins associated with memory retrieval, through reduced proteolytic activity, is associated with age-related impairments in memory retention.

scholarly journals BENEFICIAL EFFECTS OF A PLASMA FRACTION ON NEUROGENESIS FOR AGE-RELATED COGNITIVE DISORDERS

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S90-S91
Author(s):  
Ian Gallager ◽  
Viktoria Kheifets ◽  
S Sakura Minami ◽  
Eva Czirr ◽  
scott lohr ◽  
...  
Keyword(s):  
Human Plasma ◽  
Cognitive Disorders ◽  
Hippocampal Neurogenesis ◽  
Brain Inflammation ◽  
Global Changes ◽  
Beneficial Effects ◽  
Protein Levels ◽  
Plasma Fraction ◽  
Age Related ◽  
Organ Systems

Abstract The process of aging is multifactorial and therefore single interventions may be unlikely to attenuate the myriad pathologies. Plasma contains many beneficial factors which have been shown in animal models to ameliorate multiple age-related deficits across varied organ systems, including the brain. We demonstrated that human plasma from young 18-22-year-old donors reverses age-related cognitive decline and enhances hippocampal neurogenesis and cell survival in aged immunocompromised mice, while plasma from aged individuals (62-68 years old) has detrimental effects in young mice. Utilizing cell-based assays we identified a human plasma fraction (PF) which enhanced neuronal outgrowth and synaptic connectivity. We demonstrate that PF administration provides benefits beyond those observed with whole plasma treatment, resulting in decreased brain inflammation, increased synaptic density and neuronal activation. We evaluated longitudinal treatment of PF and observed no depletion in stem cell populations while maintaining an enhanced level of neurogenesis. We examined PF in an α-synuclein mouse model of Parkinson’s disease, where treatment significantly reversed functional, inflammatory, and neuronal deficits. To further our understanding of interplay between multiple mechanisms inducing neurogenesis, we examined the effect of exercise on PF treated mice and observed a synergistic increase in neurogenesis. Proteomic analysis of mouse plasma following PF treatment demonstrates differential protein levels compared to running or the combination of running and PF, suggesting that PF is mechanistically different from the effect of running. In summary, we demonstrate that PF is a multifactorial and multimodal, clinically-relevant, intervention for the treatment of global changes induced by aging.

scholarly journals Alterations of Nigral Dopamine Levels in Parkinson’s Disease after Environmental Enrichment and PACAP Treatment in Aging Rats

Life ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 35
Author(s):  
Adel Jungling ◽  
Dora Reglodi ◽  
Gabor Maasz ◽  
Zita Zrinyi ◽  
Janos Schmidt ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Environmental Enrichment ◽  
Sandwich Elisa ◽  
Neuroprotective Effects ◽  
Beneficial Effects ◽  
Protein Levels ◽  
Age Related ◽  
Pituitary Adenylate Cyclase ◽  
Disease Protein

The neuroprotective effects of environmental enrichment and PACAP (pituitary adenylate cyclase-activating polypeptide) are well-described in Parkinson’s disease. The aim of our study is to investigate the beneficial effects of these factors in aging parkinsonian rats. Newborn Wistar rats were divided into standard and enriched groups according to their environmental conditions. Standard animals were raised under regular conditions. During the first five postnatal weeks, enriched pups were placed in larger cages with different objects. Aging animals received (1) saline, (2) 6-hydroxidopamine (6-OHDA), or (3) 6-OHDA + PACAP injections into the left substantia nigra (s.n.). On the seventh postoperative day, the left and right s.n. were collected. The s.n. of young and aging unoperated animals were also examined in our experiment. We determined the dopamine (DA) levels by the HPLC-MS technique, while the sandwich ELISA method was used to measure the Parkinson disease protein 7 (PARK7) protein levels. In healthy animals, we found an age-related decrease of DA levels. In aging parkinsonian-enriched rats, the operation did not result in a significant DA loss. PACAP treatment could prevent the DA loss in both the standard and enriched groups. All injured PACAP-treated rats showed remarkably higher protective PARK7 levels. The protective effect of PACAP correlated with the increase of the DA and PARK7 levels.

scholarly journals NAD(P)H oxidase-derived reactive oxygen species contribute to age-related impairments of endothelium-dependent dilation in rat soleus feed arteries

2011 ◽  
Vol 110 (5) ◽  
pp. 1171-1180 ◽  
Author(s):  
Daniel W. Trott ◽  
John W. Seawright ◽  
Meredith J. Luttrell ◽  
Christopher R. Woodman
Keyword(s):  
Reactive Oxygen Species ◽  
Reactive Oxygen ◽  
Immunoblot Analysis ◽  
Oxidase Inhibitor ◽  
Oxygen Species ◽  
Fischer 344 ◽  
Young Rats ◽  
Age Related ◽  
Old Rats ◽  
Feed Arteries

We tested the hypothesis that age-related endothelial dysfunction in rat soleus muscle feed arteries (SFA) is mediated in part by NAD(P)H oxidase-derived reactive oxygen species (ROS). SFA from young (4 mo) and old (24 mo) Fischer 344 rats were isolated and cannulated for examination of vasodilator responses to flow and acetylcholine (ACh) in the absence or presence of a superoxide anion (O2−) scavenger (Tempol; 100 μM) or an NAD(P)H oxidase inhibitor (apocynin; 100 μM). In the absence of inhibitors, flow- and ACh-induced dilations were attenuated in SFA from old rats compared with young rats. Tempol and apocynin improved flow- and ACh-induced dilation in SFA from old rats. In SFA from young rats, Tempol and apocynin had no effect on flow-induced dilation, and apocynin attenuated ACh-induced dilation. To determine the role of hydrogen peroxide (H2O2), dilator responses were assessed in the absence and presence of catalase (100 U/ml) or PEG-catalase (200 U/ml). Neither H2O2 scavenger altered flow-induced dilation, whereas both H2O2 scavengers blunted ACh-induced dilation in SFA from young rats. In old SFA, catalase improved flow-induced dilation whereas PEG-catalase improved ACh-induced dilation. Compared with young SFA, in response to exogenous H2O2 and NADPH, old rats exhibited blunted dilation and constriction, respectively. Immunoblot analysis revealed that the NAD(P)H oxidase subunit gp91phox protein content was greater in old SFA compared with young. These results suggest that NAD(P)H oxidase-derived reactive oxygen species contribute to impaired endothelium-dependent dilation in old SFA.

scholarly journals Aging and estrogen alter endothelial reactivity to reactive oxygen species in coronary arterioles

2011 ◽  
Vol 300 (6) ◽  
pp. H2105-H2115 ◽  
Author(s):  
Lori S. Kang ◽  
Bei Chen ◽  
Rafael A. Reyes ◽  
Amanda J. LeBlanc ◽  
Bunyen Teng ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Reactive Oxygen ◽  
Immunoblot Analysis ◽  
Female Rats ◽  
No Production ◽  
Oxygen Species ◽  
Ovx Rats ◽  
Before And After ◽  
Coronary Arterioles ◽  
Reduced Flow

Endothelium-dependent, nitric oxide (NO)-mediated vasodilation can be impaired by reactive oxygen species (ROS), and this deleterious effect of ROS on NO availability may increase with aging. Endothelial function declines rapidly after menopause, possibly because of loss of circulating estrogen and its antioxidant effects. The purpose of the current study was to determine the role of O2−and H2O2in regulating flow-induced dilation in coronary arterioles of young (6-mo) and aged (24-mo) intact, ovariectomized (OVX), or OVX + estrogen-treated (OVE) female Fischer 344 rats. Both aging and OVX reduced flow-induced NO production, whereas flow-induced H2O2production was not altered by age or estrogen status. Flow-induced vasodilation was evaluated before and after treatment with the superoxide dismutase (SOD) mimetic Tempol (100 μM) or the H2O2scavenger catalase (100 U/ml). Removal of H2O2with catalase reduced flow-induced dilation in all groups, whereas Tempol diminished vasodilation in intact and OVE, but not OVX, rats. Immunoblot analysis revealed elevated nitrotyrosine with aging and OVX. In young rats, OVX reduced SOD protein while OVE increased SOD in aged rats; catalase protein did not differ in any group. Collectively, these studies suggest that O2−and H2O2are critical components of flow-induced vasodilation in coronary arterioles from female rats; however, a chronic deficiency of O2−buffering by SOD contributes to impaired flow-induced dilation with aging and loss of estrogen. Furthermore, these data indicate that estrogen replacement restores O2−homeostasis and flow-induced dilation of coronary arterioles, even at an advanced age.

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