Superoxide‐lowering therapy with TEMPOL reverses arterial dysfunction with aging in mice

Fleenor, Bradley S.; Seals, Douglas R.; Zigler, Melanie C.; Sindler, Amy L.

doi:10.1111/j.1474-9726.2011.00783.x

Cited by 113 publications

(137 citation statements)

References 44 publications

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“…These function‐based observations are supported by our direct assessments of arterial superoxide production using EPR spectroscopy, as well as our results for nitrotyrosine, a well‐established cellular marker of oxidative stress (Csiszar et al ., 2002; Sindler et al ., 2011; Fleenor et al ., 2012a; Donato et al ., 2013). Aging in control animals was associated with marked increases in both aortic superoxide production and nitrotyrosine abundance (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Aging in control animals was associated with marked increases in both aortic superoxide production and nitrotyrosine abundance (Fig. 2B,C), as we have reported previously (Rippe et al ., 2010; Sindler et al ., 2011; Fleenor et al ., 2012a, 2013; Donato et al ., 2013; LaRocca et al ., 2013). In response to NMN supplementation, we observed a normalization of aortic superoxide production and a marked reduction in nitrotyrosine abundance in old mice.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, elastin, the main structural protein conferring elasticity, is reduced in old arteries (Zieman et al ., 2005; Diez, 2007; Fleenor et al ., 2012b). We have previously shown in mice (Fleenor et al ., 2012a) and cultured aortic fibroblasts (Fleenor et al ., 2010) that oxidative stress contributes to some or all of the age‐associated structural changes seen within the arteries. In the present study, we demonstrate that 8 weeks of NMN supplementation reverses the accumulation of whole‐vessel collagen type I and enhances arterial elastin in old mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…We have observed reductions in aortic collagen in old mice subjected to other short‐term late‐life behavioral or pharmacological interventions (Fleenor et al ., 2010, 2012a, 2013; LaRocca et al ., 2013), although not in every case (Fleenor et al ., 2012b). Interestingly, NMN also induced a partial restoration of aortic elastin to levels not significantly different from young control animals.…”

Section: Discussionmentioning

confidence: 99%

“…A common mechanism that contributes to both vascular endothelial dysfunction and large elastic artery stiffness with aging is excessive superoxide‐associated vascular oxidative stress (Seals et al ., 2011; Fleenor et al ., 2012a; Bachschmid et al ., 2013). Increased vascular production of superoxide occurs with aging and reduces the bioavailability of the vasoprotective and vasodilatory molecule nitric oxide (NO), while also causing alterations in major structural proteins (collagen and elastin) in the large elastic arteries (i.e., the aorta and carotid arteries) (Deanfield et al ., 2007; Fleenor et al ., 2010; Seals et al ., 2014).…”

Section: Introductionmentioning

confidence: 99%

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Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice

et al. 2016

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SummaryWe tested the hypothesis that supplementation of nicotinamide mononucleotide (NMN), a key NAD + intermediate, increases arterial SIRT1 activity and reverses age‐associated arterial dysfunction and oxidative stress. Old control mice (OC) had impaired carotid artery endothelium‐dependent dilation (EDD) (60 ± 5% vs. 84 ± 2%), a measure of endothelial function, and nitric oxide (NO)‐mediated EDD (37 ± 4% vs. 66 ± 6%), compared with young mice (YC). This age‐associated impairment in EDD was restored in OC by the superoxide (O2−) scavenger TEMPOL (82 ± 7%). OC also had increased aortic pulse wave velocity (aPWV, 464 ± 31 cm s−1 vs. 337 ± 3 cm s−1) and elastic modulus (EM, 6407 ± 876 kPa vs. 3119 ± 471 kPa), measures of large elastic artery stiffness, compared with YC. OC had greater aortic O2− production (2.0 ± 0.1 vs. 1.0 ± 0.1 AU), nitrotyrosine abundance (a marker of oxidative stress), and collagen‐I, and reduced elastin and vascular SIRT1 activity, measured by the acetylation status of the p65 subunit of NFκB, compared with YC. Supplementation with NMN in old mice restored EDD (86 ± 2%) and NO‐mediated EDD (61 ± 5%), reduced aPWV (359 ± 14 cm s−1) and EM (3694 ± 315 kPa), normalized O2− production (0.9 ± 0.1 AU), decreased nitrotyrosine, reversed collagen‐I, increased elastin, and restored vascular SIRT1 activity. Acute NMN incubation in isolated aortas increased NAD + threefold and manganese superoxide dismutase (MnSOD) by 50%. NMN supplementation may represent a novel therapy to restore SIRT1 activity and reverse age‐related arterial dysfunction by decreasing oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice

et al. 2016

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Anthracycline chemotherapy‐mediated vascular dysfunction as a model of accelerated vascular aging

et al. 2021

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Cardiovascular diseases (CVD) are the leading cause of death worldwide, and age is by far the greatest risk factor for developing CVD. Vascular dysfunction, including endothelial dysfunction and arterial stiffening, is responsible for much of the increase in CVD risk with aging. A key mechanism involved in vascular dysfunction with aging is oxidative stress, which reduces the bioavailability of nitric oxide (NO) and induces adverse changes to the extracellular matrix of the arterial wall (e.g., elastin fragmentation/degradation, collagen deposition) and an increase in advanced glycation end products, which form crosslinks in arterial wall structural proteins. Although vascular dysfunction and CVD are most prevalent in older adults, several conditions can "accelerate" these events at any age. One such factor is chemotherapy with anthracyclines, such as doxorubicin (DOXO), to combat common forms of cancer. Children, adolescents, and young adults treated with these chemotherapeutic agents demonstrate impaired vascular function and an increased risk of future CVD development compared with healthy age-matched controls. Anthracycline treatment also worsens vascular dysfunction in midlife (50-64 years of age) and older (65 and older) adults such that endothelial dysfunction and arterial stiffness are greater compared to agematched controls. Collectively, these observations indicate that use of anthracycline chemotherapeutic agents induces a vascular aging-like phenotype and that the latter contributes to premature CVD in cancer survivors exposed to these agents. Here, we review the existing literature supporting these ideas, discuss potential mechanisms as well as interventions that may protect arteries from these adverse effects, identify research gaps, and make recommendations for future research.

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EFFECT OF TEMPOL ON REDOX HOMEOSTASIS AND STRESS TOLERANCE IN MIMETICALLY AGED DROSOPHILA

Aksu

Yanar

Terzioglu

et al. 2014

Arch Insect Biochem Physiol

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We aimed to test our hypothesis that scavenging reactive oxygen species (ROS) with tempol, a membrane permeable antioxidant, affects the type and magnitude of oxidative damage and stress tolerance through mimetic aging process in Drosophila. Drosophila colonies were randomly divided into three groups: (1) no D-galactose, no tempol; (2) D-galactose without tempol; (3) D-galactose, but with tempol. Mimetic aging was induced by d-galactose administration. The tempol-administered flies received tempol at the concentration of 0.2% in addition to d-galactose. Thiobarbituric acid reacting substance (TBARS) concentrations, advanced oxidation protein products (AOPPs), Cu,Zn-superoxide dismutase (Cu,Zn-SOD), sialic acid (SA) were determined. Additionally, stress tolerances were tested. Mimetically aged group without tempol led to a significant decrease in tolerance to heat, cold, and starvation (P < 0.05), but tempol was used for these parameters. The Cu,Zn-SOD activity and SA concentrations were lower in both mimetically aged and tempol-administered Drosophila groups compared to control (P < 0.05), whereas there were no significantly difference between mimetically aged and tempol-administered groups. Mimetically aged group without tempol led to a significant increase in tissue TBARS and AOPPs concentrations (P < 0.05). Coadministration of tempol could prevent these alterations. Scavenging ROS using tempol also restores redox homeostasis in mimetically aged group. Tempol partly restores age-related oxidative injury and increases stress tolerance.

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Superoxide‐lowering therapy with TEMPOL reverses arterial dysfunction with aging in mice

Cited by 113 publications

References 44 publications

Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice

Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice

Anthracycline chemotherapy‐mediated vascular dysfunction as a model of accelerated vascular aging

EFFECT OF TEMPOL ON REDOX HOMEOSTASIS AND STRESS TOLERANCE IN MIMETICALLY AGED DROSOPHILA

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