scholarly journals Inorganic nitrite supplementation for healthy arterial aging

2014 ◽  
Vol 116 (5) ◽  
pp. 463-477 ◽  
Author(s):  
Amy L. Sindler ◽  
Allison E. DeVan ◽  
Bradley S. Fleenor ◽  
Douglas R. Seals
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Therapeutic Potential ◽  
Vascular Dysfunction ◽  
Aortic Pulse Wave Velocity ◽  
Vascular Aging ◽  
Age Related ◽  
Arterial Aging ◽  
Artery Stiffness ◽  
Elastic Artery

Aging is the major risk factor for cardiovascular diseases (CVD). This is attributable primarily to adverse changes in arteries, notably, increases in large elastic artery stiffness and endothelial dysfunction mediated by inadequate concentrations of the vascular-protective molecule, nitric oxide (NO), and higher levels of oxidative stress and inflammation. Inorganic nitrite is a promising precursor molecule for augmenting circulating and tissue NO bioavailability because it requires only a one-step reduction to NO. Nitrite also acts as an independent signaling molecule, exerting many of the effects previously attributed to NO. Results of recent studies indicate that nitrite may be effective in the treatment of vascular aging. In old mice, short-term oral sodium nitrite supplementation reduces aortic pulse wave velocity, the gold-standard measure of large elastic artery stiffness, and ameliorates endothelial dysfunction, as indicated by normalization of NO-mediated endothelium-dependent dilation. These improvements in age-related vascular dysfunction with nitrite are mediated by reductions in oxidative stress and inflammation, and may be linked to increases in mitochondrial biogenesis and health. Increasing nitrite levels via dietary intake of nitrate appears to have similarly beneficial effects in many of the same physiological and clinical settings. Several clinical trials are being performed to determine the broad therapeutic potential of increasing nitrite bioavailability on human health and disease, including studies related to vascular aging. In summary, inorganic nitrite, as well as dietary nitrate supplementation, represents a promising therapy for treatment of arterial aging and prevention of age-associated CVD in humans.

Vascular and Endothelial Biology of Aging

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. SCI-5-SCI-5
Author(s):  
Frank M. Faraci
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Transgenic Mice ◽  
Nadph Oxidase ◽  
Endothelial Function ◽  
Vascular Dysfunction ◽  
Rho Kinase ◽  
Vascular Aging ◽  
Age Related ◽  
The Brain

Abstract Although aging is one of the greatest risk factors for vascular disease, very little is known regarding mechanisms that control the progression of vascular aging at the level of the endothelial cell. Endothelial dysfunction - a critical element of carotid artery and cerebrovascular disease - progresses with age, contributing to hypoperfusion, increased risk for ischemic stroke, and cognitive decline. Studies from several laboratories support the concept that age-induced endothelial dysfunction may occur earlier and be larger in magnitude in the cerebral circulation than in blood vessels outside of the brain. Thus, the circulationof the brain may be particularly sensitive to age-induced endothelial dysfunction. In relation to underlying mechanisms, angiotensin II type 1 receptors, NADPH oxidase, and oxidative stress appear to play a key role in age-related vascular dysfunction. The nuclear receptor peroxisome proliferator-activated receptor-g (PPARg) exerts protective effects in the vasculature when pharmacologically activated. We recently examined the hypothesis that endothelial PPARg protects against vascular aging. We studied carotid arteries from adult and old transgenic mice with endothelial specific expression of a human dominant negative mutation in PPARg driven by the vascular cadherin promoter (designated E-V290M), along with non-transgenic littermates. Endothelial function was similar in arteries from adult non-transgenic and E-V290M mice as well as old non-transgenic mice. In contrast, there was a marked reduction in endothelial function in old E-V290M mice. This augmented endothelial dysfunction was not altered by inhibition of cyclooxygenase, but was restored to normal by a superoxide scavenger, an inhibitor of NADPH oxidase, or inhibition of Rho kinase. Oxidant and inflammatory related mechanisms often interact. Vascular expression of interleukin-6, another mediator of vascular disease, was increased 1.6-fold in old non-transgenic mice, but almost 9-fold in old E-V290M mice. Expression of CDKN2A, a molecular marker of senescence, was ~two-fold greater in old E-V290M mice compared to controls. These findings provide the first evidence that senescence and age-related vascular dysfunction is accelerated following cell-specific interference with endothelial PPARg through mechanisms that involve oxidative stress, inflammation, and Rho kinase. This critical role for endothelial PPARg has implications for vascular pathophysiology as well as therapeutic approaches for age-induced large and small vessel disease. Disclosures No relevant conflicts of interest to declare.

Abstract T MP114: PPARγ in Endothelial Cells Plays an Essential Role in Protecting Against Vascular Aging: Role of Oxidative Stress and Rho Kinase

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Dale Kinzenbaw ◽  
T. Micheal De Silva ◽  
Curt Sigmund ◽  
Frank M Faraci
Keyword(s):  
Oxidative Stress ◽  
Endothelial Function ◽  
Vascular Disease ◽  
Vascular Dysfunction ◽  
Rho Kinase ◽  
Dominant Negative ◽  
Vascular Aging ◽  
Dominant Negative Mutation ◽  
Age Related

Although aging is the greatest risk factor for vascular disease and stroke, relatively little is known regarding mechanisms that regulate vascular aging. Endothelial dysfunction - a key element of carotid artery and cerebrovascular disease - progresses with age, greatly increasing the risk for ischemic stroke and cognitive impairment. The nuclear receptor peroxisome proliferator activated receptor-γ (PPARγ) is a ligand-activated transcription factor that may exert diverse effects depending on the cell type. Because little is known regarding the role of PPARγ in vascular aging, we used transgenic mice expressing a dominant negative mutation in human PPARγ (V290M) under control of the endothelial-specific vascular cadherin promoter (designated E-V290M) to examine the hypothesis that cell-specific interference with PPARγ would promote age-induced vascular dysfunction. Responses of carotid arteries from adult (11-12 mo) and old (24±1 mo) E-V290M mice and non-transgenic littermates were examined in vitro. Acetylcholine (an endothelium-dependent agonist) produced similar relaxation of arteries from adult control and E-V290M mice as well as old control mice. In contrast, responses to acetylcholine in arteries from old E-V290M mice were reduced by more than 50% in old E-V290M mice (P<0.01). Endothelial function in old E-V290M mice was not altered by indomethacin but was restored to normal by tempol (a superoxide scavenger) or VAS-2870 (an inhibitor of NADPH oxidase). Reactive oxygen species can activate Rho kinase (a potential mediator of vascular disease) and inhibition of Rho kinase with Y-27632 restored endothelial function to normal in old E-V290M mice. Relaxation of arteries to nitroprusside, which acts directly on vascular muscle, was similar in all groups. These findings provide the first evidence that age-related vascular dysfunction is accelerated following cell-specific interference with endothelial PPARγ through mechanisms involving oxidative stress and Rho kinase. This novel role for endothelial PPARγ has implications for understanding vascular pathophysiology as well as therapeutic approaches for age-induced large and small vessel disease.

Oxidative stress and inflammation are associated with age-related endothelial dysfunction in men with low testosterone

2021 ◽  
Author(s):  
Matthew C Babcock ◽  
Lyndsey E DuBose ◽  
Teresa L Witten ◽  
Brian L Stauffer ◽  
Kerry L Hildreth ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Vitamin C ◽  
Density Lipoprotein ◽  
Saline Control ◽  
Vascular Aging ◽  
Cvd Risk ◽  
Cross Sectional ◽  
Age Related ◽  
Low Testosterone

Abstract Context Vascular aging, including endothelial dysfunction secondary to oxidative stress and inflammation, increases the risk for age-associated cardiovascular disease (CVD). Low testosterone in middle-age and older (MA/O) men is associated with increased CVD risk. Objectives We hypothesized that low testosterone contributes to age-associated endothelial dysfunction, related in part to greater oxidative stress and inflammation. Design Cross-sectional. Participants Fifty-eight healthy, non-smoking men categorized as young (N=20; age: 29±4 years, testosterone: 500±58 ng/dL), MA/O with higher testosterone (N=20; age: 60±6 years, testosterone: 512±115 ng/dL), and MA/O lower testosterone (N=18; age 59±8 years, testosterone: 269±48 ng/dL). Main Outcome Measures Brachial artery flow-mediated dilation (FMDBA) measured during acute infusion of saline (control) and vitamin C (antioxidant). Markers of oxidative stress (total antioxidant status [TAS] and oxidized low-density lipoprotein [LDL] cholesterol), inflammation (interleukin [IL]-6 and C-reactive protein [CRP]), and androgen deficiency symptoms were also examined. RESULTS: During saline, FMDBA was reduced in MA/O compared to young, regardless of testosterone status (P&lt;0.001). FMDBA was reduced in MA/O lower testosterone (3.7±2.0%) compared to MA/O higher testosterone (5.7±2.2%, p=0.021), independent of symptoms. Vitamin C increased FMDBA (to 5.3±1.6%, p=0.022) in MA/O lower testosterone but had no effect in young (P=0.992) or MA/O higher testosterone (P=0.250). FMDBA correlated with serum testosterone (r=0.45, p&lt;0.001), IL-6 (r=-0.41, P=0.002), and CRP (r=-0.28, P=0.041). Conclusions Healthy MA/O men with low testosterone appear to have greater age-associated endothelial dysfunction, related in part to greater oxidative stress and inflammation. These data suggest that low testosterone concentrations may contribute to accelerated vascular aging in men.

scholarly journals Role of endothelial NAD+ deficiency in age-related vascular dysfunction

2019 ◽  
Vol 316 (6) ◽  
pp. H1253-H1266 ◽  
Author(s):  
Anna Csiszar ◽  
Stefano Tarantini ◽  
Andriy Yabluchanskiy ◽  
Priya Balasubramanian ◽  
Tamas Kiss ◽  
...  
Keyword(s):  
Older Adults ◽  
Molecular Mechanisms ◽  
Cardiovascular Health ◽  
Therapeutic Potential ◽  
Vascular Dysfunction ◽  
Model Organisms ◽  
Vascular Aging ◽  
Health Span ◽  
Comprehensive Overview ◽  
Age Related

Age-related alterations in endothelium and the resulting vascular dysfunction critically contribute to a range of pathological conditions associated with old age. To develop therapies rationally that improve vascular health and thereby increase health span and life span in older adults, it will be essential to understand the cellular and molecular mechanisms contributing to vascular aging. Preclinical studies in model organisms demonstrate that NAD+ availability decreases with age in multiple tissues and that supplemental NAD+ precursors can ameliorate many age-related cellular impairments. Here, we provide a comprehensive overview of NAD+-dependent pathways [including the NAD+-using silent information regulator-2-like enzymes and poly(ADP-ribose) polymerase enzymes] and the potential consequences of endothelial NAD+ deficiency in vascular aging. The multifaceted vasoprotective effects of treatments that reverse the age-related decline in cellular NAD+ levels, as well as their potential limitations, are discussed. The preventive and therapeutic potential of NAD+ intermediates as effective, clinically relevant interventions in older adults at risk for ischemic heart disease, vascular cognitive impairment, and other common geriatric conditions and diseases that involve vascular pathologies (e.g., sarcopenia, frailty) are critically discussed. We propose that NAD+ precursors [e.g., nicotinamide (Nam) riboside, Nam mononucleotide, niacin] should be considered as critical components of combination therapies to slow the vascular aging process and increase cardiovascular health span.

Abstract 108: Cell-Specific Interference with Endothelial PPARγ Produces Oxidative Stress and Accelerates Vascular Aging

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Mary L Modrick ◽  
Dale A Kinzenbaw ◽  
Pimonrat Ketsawatsomkron ◽  
Curt D Sigmund ◽  
Frank M Faraci
Keyword(s):  
Oxidative Stress ◽  
Carotid Artery ◽  
Vascular Disease ◽  
Carotid Arteries ◽  
Vascular Dysfunction ◽  
Dominant Negative ◽  
Nitric Oxide Donor ◽  
Vascular Aging ◽  
Dominant Negative Mutation ◽  
Age Related

Despite the fact that aging is the greatest risk factor for vascular disease and stroke, relatively little is known regarding mechanisms that promote or protect against vascular aging in experimental models or people. Endothelial dysfunction is a key contributor to both the initiation and progression of vascular disease. Atherosclerosis in carotid arteries (carotid artery disease) greatly increases the risk for ischemic stroke and may contribute to dementia (including Alzheimer’s disease). Peroxisome proliferator activated receptor-γ (PPARγ) is a ligand-activated transcription factor that exerts diverse effects depending on the cell type. Recent work suggests that PPARγ can have beneficial effects in the vasculature including protection against oxidative stress. Relatively little is known regarding the potential role of PPARγ in aging. We used transgenic mice expressing a dominant negative mutation in human PPARγ (V290M) under control of the endothelial-specific vascular cadherin promoter (designated E-V290M) to examine the hypothesis that interference with endothelial PPARγ will promote age-induced vascular dysfunction. Responses of carotid arteries from adult (6±1 mo) and old (23±1 mo) E-V290M mice and non-transgenic littermates (controls) were examined in vitro. Acetylcholine (an endothelium-dependent agonist) produced similar relaxation of arteries from adult control and E-V290M mice as well as old control mice. In contrast, responses to acetylcholine in arteries from old E-V290M mice were markedly impaired. For example, relaxation of the carotid artery to 10 µmol/L acetylcholine was 84±3 and 40±6% in old control versus old E-V290M mice, respectively (P<0.01). The impaired response to acetylcholine in old E-V290M mice could be restored to normal (81±4% relaxation) by tempol, a scavenger of superoxide. Relaxation of the carotid artery to nitroprusside (a nitric oxide donor that acts directly on vascular muscle) was similar in all groups. These findings provide the first evidence that age-related vascular dysfunction is accelerated following cell-specific interference with endothelial PPARγ function. The mechanism that accounts for this change appears to involve reactive oxygen species. Our findings suggest a major protective role for endothelial PPARγ in age-induced oxidative stress and vascular dysfunction.

scholarly journals Targeting mitochondrial fitness as a strategy for healthy vascular aging

2020 ◽  
Vol 134 (12) ◽  
pp. 1491-1519 ◽  
Author(s):  
Matthew J. Rossman ◽  
Rachel A. Gioscia-Ryan ◽  
Zachary S. Clayton ◽  
Michael P. Murphy ◽  
Douglas R. Seals
Keyword(s):  
Oxidative Stress ◽  
Carotid Arteries ◽  
Vascular Dysfunction ◽  
Current Evidence ◽  
Vascular Aging ◽  
Cvd Risk ◽  
Age Related ◽  
Vascular Oxidative Stress ◽  
Primary Risk Factor ◽  
Related Increase

Abstract Cardiovascular diseases (CVD) are the leading cause of death worldwide and aging is the primary risk factor for CVD. The development of vascular dysfunction, including endothelial dysfunction and stiffening of the large elastic arteries (i.e., the aorta and carotid arteries), contribute importantly to the age-related increase in CVD risk. Vascular aging is driven in large part by oxidative stress, which reduces bioavailability of nitric oxide and promotes alterations in the extracellular matrix. A key upstream driver of vascular oxidative stress is age-associated mitochondrial dysfunction. This review will focus on vascular mitochondria, mitochondrial dysregulation and mitochondrial reactive oxygen species (ROS) production and discuss current evidence for prevention and treatment of vascular aging via lifestyle and pharmacological strategies that improve mitochondrial health. We will also identify promising areas and important considerations (‘research gaps’) for future investigation.

scholarly journals Telomere uncapping and vascular aging

2018 ◽  
Vol 315 (1) ◽  
pp. H1-H5 ◽  
Author(s):  
R. Garrett Morgan ◽  
Anthony J. Donato ◽  
Ashley E. Walker
Keyword(s):  
Oxidative Stress ◽  
Cellular Senescence ◽  
Vascular Dysfunction ◽  
Vascular Aging ◽  
Telomere Shortening ◽  
Biologically Relevant ◽  
Double Stranded Dna ◽  
Age Related ◽  
Damage Response ◽  
Telomere Biology

Although most telomere biology research continues to focus on telomere shortening, there is increasing evidence that telomere deprotection, or “uncapping,” is more biologically and possibly clinically important. Telomeres form t-loops to prevent the chromosome ends from appearing as a double-stranded DNA break and initiating a DNA damage response. Breakdown of the t-loop structure, referred to as uncapping, can lead to cellular senescence, increased oxidative stress, and inflammation in tissues. In this review, we describe how telomere uncapping potentially leads to age-related vascular dysfunction and increased cellular senescence, oxidative stress, and inflammation. Importantly, we present evidence to argue that telomere uncapping is more biologically relevant than telomere shortening and a better marker of vascular aging and target for antiaging interventions.

scholarly journals Vascular Aging across the Menopause Transition in Healthy Women

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Kerrie L. Moreau ◽  
Kerry L. Hildreth
Keyword(s):  
Endothelial Dysfunction ◽  
Postmenopausal Women ◽  
Endurance Exercise ◽  
Ovarian Function ◽  
Future Research ◽  
Large Artery ◽  
Vascular Aging ◽  
Age Related ◽  
Artery Stiffness ◽  
Menopause Transition

Vascular aging, featuring endothelial dysfunction and large artery stiffening, is a major risk factor for developing cardiovascular disease (CVD). In women, vascular aging appears to be accelerated during the menopause transition, particularly around the late perimenopausal period, presumably related to declines in ovarian function and estrogen levels. The mechanisms underlying endothelial dysfunction and large artery stiffening with the menopause transition are not completely understood. Oxidative stress and the proinflammatory cytokine tumor necrosis factor-α contribute to endothelial dysfunction and large artery stiffening in estrogen-deficient postmenopausal women. Habitual endurance exercise attenuates the age-related increase in large artery stiffness in estrogen-deficient postmenopausal women and can reverse arterial stiffening to premenopausal levels in estrogen-replete postmenopausal women. In contrast, estrogen status appears to play a key permissive role in the adaptive response of the endothelium to habitual endurance exercise in that endothelial improvements are absent in estrogen-deficient women but present in estrogen-replete women. We review here the current state of knowledge on the biological defects underlying vascular aging across the menopause transition, with particular focus on potential mechanisms, the role of habitual exercise in preserving vascular health, and key areas for future research.

scholarly journals Age-Related Macular Degeneration: Role of Oxidative Stress and Blood Vessels

2021 ◽  
Vol 22 (3) ◽  
pp. 1296
Author(s):  
Yue Ruan ◽  
Subao Jiang ◽  
Adrian Gericke
Keyword(s):  
Oxidative Stress ◽  
Macular Degeneration ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Therapeutic Strategies ◽  
Vision Impairment ◽  
Age Related Macular Degeneration ◽  
Oxygen Species ◽  
Age Related

Age-related macular degeneration (AMD) is a common irreversible ocular disease characterized by vision impairment among older people. Many risk factors are related to AMD and interact with each other in its pathogenesis. Notably, oxidative stress and choroidal vascular dysfunction were suggested to be critically involved in AMD pathogenesis. In this review, we give an overview on the factors contributing to the pathophysiology of this multifactorial disease and discuss the role of reactive oxygen species and vascular function in more detail. Moreover, we give an overview on therapeutic strategies for patients suffering from AMD.

Low-dose aspirin prevents age-related endothelial dysfunction in a mouse model of physiological aging

2008 ◽  
Vol 294 (4) ◽  
pp. H1562-H1570 ◽  
Author(s):  
Hélène Bulckaen ◽  
Gaétan Prévost ◽  
Eric Boulanger ◽  
Géraldine Robitaille ◽  
Valérie Roquet ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Protective Effect ◽  
Structural Changes ◽  
Low Dose ◽  
Age Groups ◽  
Dose Aspirin ◽  
Age Related ◽  
Low Dose Aspirin ◽  
Old Mice

The age-related impairment of endothelium-dependent vasodilatation contributes to increased cardiovascular risk in the elderly. For primary and secondary prevention, aspirin can reduce the incidence of cardiovascular events in this patient population. The present work evaluated the effect of low-dose aspirin on age-related endothelial dysfunction in C57B/J6 aging mice and investigated its protective antioxidative effect. Age-related endothelial dysfunction was assessed by the response to acetylcholine of phenylephrine-induced precontracted aortic segments isolated from 12-, 36-, 60-, and 84-wk-old mice. The effect of low-dose aspirin was examined in mice presenting a decrease in endothelial-dependent relaxation (EDR). The effects of age and aspirin treatment on structural changes were determined in mouse aortic sections. The effect of aspirin on the oxidative stress markers malondialdehyde and 8-hydroxy-2′-deoxyguanosine (8-OhdG) was also quantified. Compared with that of 12-wk-old mice, the EDR was significantly reduced in 60- and 84-wk-old mice ( P < 0.05); 68-wk-old mice treated with aspirin displayed a higher EDR compared with control mice of the same age (83.9 ± 4 vs. 66.3 ± 5%; P < 0.05). Aspirin treatment decreased 8-OHdG levels ( P < 0.05), but no significant effect on intima/media thickness ratio was observed. The protective effect of aspirin was not observed when treatment was initiated in older mice (96 wk of age). It was found that low-dose aspirin is able to prevent age-related endothelial dysfunction in aging mice. However, the absence of this effect in the older age groups demonstrates that treatment should be initiated early on. The underlying mechanism may involve the protective effect of aspirin against oxidative stress.

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