Targeting mitochondrial fitness as a strategy for healthy vascular aging

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.

Download Full-text

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

Stroke ◽

10.1161/str.43.suppl_1.a108 ◽

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.

Download Full-text

ET-1 as a Sex-Specific Mechanism Impacting Age-Related Changes in Vascular Function

Frontiers in Aging ◽

10.3389/fragi.2021.727416 ◽

2021 ◽

Vol 2 ◽

Author(s):

Andrew V. Kuczmarski ◽

Laura M. Welti ◽

Kerrie L. Moreau ◽

Megan M. Wenner

Keyword(s):

Sex Differences ◽

Vascular Function ◽

Cardiovascular Health ◽

Vascular Dysfunction ◽

Developed Countries ◽

Therapeutic Interventions ◽

Vascular Aging ◽

Cvd Risk ◽

Men And Women ◽

Age Related

Aging is a primary risk factor for cardiovascular disease (CVD), which is the leading cause of death in developed countries. Globally, the population of adults over the age of 60 is expected to double by the year 2050. CVD prevalence and mortality rates differ between men and women as they age in part due to sex-specific mechanisms impacting the biological processes of aging. Measures of vascular function offer key insights into cardiovascular health. Changes in vascular function precede changes in CVD prevalence rates in men and women and with aging. A key mechanism underlying these changes in vascular function is the endothelin (ET) system. Studies have demonstrated sex and sex hormone effects on endothelin-1 (ET-1), and its receptors ETA and ETB. However, with aging there is a dysregulation of this system resulting in an imbalance between vasodilation and vasoconstriction. Thus, ET-1 may play a role in the sex differences observed with vascular aging. While most research has been conducted in pre-clinical animal models, we describe more recent translational data in humans showing that the ET system is an important regulator of vascular dysfunction with aging and acts through sex-specific ET receptor mechanisms. In this review, we present translational evidence (cell, tissue, animal, and human) that the ET system is a key mechanism regulating sex-specific changes in vascular function with aging, along with therapeutic interventions to reduce ET-mediated vascular dysfunction associated with aging. More knowledge on the factors responsible for the sex differences with vascular aging allow for optimized therapeutic strategies to attenuate CVD risk in the expanding aging population.

Download Full-text

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

Stroke ◽

10.1161/str.45.suppl_1.tmp114 ◽

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.

Download Full-text

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

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab715 ◽

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<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<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.

Download Full-text

Vascular and Endothelial Biology of Aging

Blood ◽

10.1182/blood.v126.23.sci-5.sci-5 ◽

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.

Download Full-text

Vascular dysfunction in cerebrovascular disease: mechanisms and therapeutic intervention

Clinical Science ◽

10.1042/cs20090649 ◽

2010 ◽

Vol 119 (1) ◽

pp. 1-17 ◽

Cited By ~ 44

Author(s):

Alyson A. Miller ◽

Klaudia Budzyn ◽

Christopher G. Sobey

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

Cerebrovascular Disease ◽

Vascular Dysfunction ◽

Rho Kinase ◽

Amyloid Β ◽

Current Evidence ◽

Underlying Causes ◽

Strong Candidate ◽

Vascular Oxidative Stress

The endothelium plays a crucial role in the control of vascular homoeostasis through maintaining the synthesis of the vasoprotective molecule NO• (nitric oxide). Endothelial dysfunction of cerebral blood vessels, manifested as diminished NO• bioavailability, is a common feature of several vascular-related diseases, including hypertension, hypercholesterolaemia, stroke, subarachnoid haemorrhage and Alzheimer's disease. Over the past several years an enormous amount of research has been devoted to understanding the mechanisms underlying endothelial dysfunction. As such, it has become apparent that, although the diseases associated with impaired NO• function are diverse, the underlying causes are similar. For example, compelling evidence indicates that oxidative stress might be an important mechanism of diminished NO• signalling in diverse models of cardiovascular ‘high-risk’ states and cerebrovascular disease. Although there are several sources of vascular ROS (reactive oxygen species), the enzyme NADPH oxidase is emerging as a strong candidate for the excessive ROS production that is thought to lead to vascular oxidative stress. The purpose of the present review is to outline some of the mechanisms thought to contribute to endothelial dysfunction in the cerebral vasculature during disease. More specifically, we will highlight current evidence for the involvement of ROS, inflammation, the RhoA/Rho-kinase pathway and amyloid β-peptides. In addition, we will discuss currently available therapies for improving endothelial function and highlight future therapeutic strategies.

Download Full-text

Inorganic nitrite supplementation for healthy arterial aging

Journal of Applied Physiology ◽

10.1152/japplphysiol.01100.2013 ◽

2014 ◽

Vol 116 (5) ◽

pp. 463-477 ◽

Cited By ~ 36

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.

Download Full-text

Telomere uncapping and vascular aging

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00008.2018 ◽

2018 ◽

Vol 315 (1) ◽

pp. H1-H5 ◽

Cited By ~ 9

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.

Download Full-text

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

International Journal of Molecular Sciences ◽

10.3390/ijms22031296 ◽

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.

Download Full-text

Curcumin Inhibits Age-Related Vascular Changes in Aged Mice Fed a High-Fat Diet

Nutrients ◽

10.3390/nu10101476 ◽

2018 ◽

Vol 10 (10) ◽

pp. 1476 ◽

Cited By ~ 8

Author(s):

Kenichiro Takano ◽

Junko Tatebe ◽

Naohiro Washizawa ◽

Toshisuke Morita

Keyword(s):

Oxidative Stress ◽

High Fat Diet ◽

Heme Oxygenase 1 ◽

Vascular Aging ◽

High Fat ◽

Sirt1 Expression ◽

Age Related ◽

Westernized Diet ◽

Term Administration ◽

Oxidative Effects

Inhibiting the onset of arteriosclerotic disease, which has been increasing due to the westernized diet and aging, is a significant social challenge. Curcumin, a type of polyphenol, has anti-oxidative effects and anti-inflammatory action and is expected to treat and to have prophylactic effects on different diseases. In this study, we examined the effects of long-term administration of curcumin on vascular aging and chronic inflammation—the causes of arteriosclerotic disease. Eight-week-old C57BL/6J mice were fed with high fat diet (HFD) or 0.1% curcumin-mixed HFD (HFD + Cu) until 80 weeks old (n = 20 for each group). After the breeding, we examined the expression of antioxidant enzymes, heme oxygenase-1 (HO-1), oxidative stress, vascular aging, and inflammatory changes in the aorta. In the HFD group, oxidative stress increased with decreased sirt1 expression in the aorta followed by increased senescent cells and enhanced inflammation. Whereas in the HFD + Cu group, HO-1 was induced in the aorta with the suppression of oxidative stress. Additionally, it was shown that sirt1 expression in the aorta in the HFD + Cu group remained at a level comparable to that of the 8-week-old mice with suppression of increased senescent cells and enhanced inflammation. Consequently, disorders associated with HFD were resolved. These results suggest that curcumin might be a food with a prophylactic function against arteriosclerotic disease.

Download Full-text