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  • 1
    Language: English
    In: The Journal of cell biology, 21 July 2014, Vol.206(2), pp.257-72
    Description: Supernumerary centrosomes contribute to spindle defects and aneuploidy at mitosis, but the effects of excess centrosomes during interphase are poorly understood. In this paper, we show that interphase endothelial cells with even one extra centrosome exhibit a cascade of defects, resulting in disrupted cell migration and abnormal blood vessel sprouting. Endothelial cells with supernumerary centrosomes had increased centrosome scattering and reduced microtubule (MT) nucleation capacity that correlated with decreased Golgi integrity and randomized vesicle trafficking, and ablation of excess centrosomes partially rescued these parameters. Mechanistically, tumor endothelial cells with supernumerary centrosomes had less centrosome-localized γ-tubulin, and Plk1 blockade prevented MT growth, whereas overexpression rescued centrosome γ-tubulin levels and centrosome dynamics. These data support a model whereby centrosome-MT interactions during interphase are important for centrosome clustering and cell polarity and further suggest that disruption of interphase cell behavior by supernumerary centrosomes contributes to pathology independent of mitotic effects.
    Keywords: Cell Movement ; Centrosome -- Physiology ; Endothelial Cells -- Ultrastructure
    ISSN: 00219525
    E-ISSN: 1540-8140
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  • 2
    In: Journal of Physiology, September 2011, Vol.589(18), pp.4545-4554
    Description: Advancing age is a major risk factor for the development of cardiovascular disease. A key characteristic of older arteries that may lead to cardiovascular disease is reduced endothelial function, characterized by blunted endothelium‐dependent dilatation. Sirtuins, specifically sirtuin‐1, are proteins linked to increases in lifespan and lower incidence of age‐related diseases. We hypothesized that diminished sirtuin‐1 with advancing age may alter regulation of a key endothelium dilatory enzyme, nitric oxide synthase. Our findings provide novel translational evidence that sirtuin‐1 expression and activity contribute to arterial endothelial dysfunction with ageing and that this may be due to altered nitric oxide synthase activation. Importantly, our results provide further compelling support for sirtuin‐1 as a potential therapeutic target for lifestyle and pharmacological interventions aimed at the prevention and treatment of arterial ageing and age‐associated cardiovascular diseases. We tested the hypothesis that reductions in the cellular deacetylase, sirtuin‐1 (SIRT‐1), contribute to vascular endothelial dysfunction with ageing via modulation of endothelial nitric oxide synthase (eNOS) acetylation/activation‐associated nitric oxide (NO) production. In older (30 months, = 14) . young (5–7 months, = 16) B6D2F1 mice, aortic protein expression of SIRT‐1 and eNOS phosphorylated at serine 1177 were lower (both 〈 0.05), and acetylated eNOS was 6‐fold higher ( 〈 0.05), whereas total eNOS did not differ (= 0.65). Acetylcholine (ACh)‐induced peak endothelium‐dependent dilatation (EDD) was lower in isolated femoral arteries with ageing ( 〈 0.001). Incubation with sirtinol, a SIRT‐1 inhibitor, reduced EDD in both young and older mice, abolishing age‐related differences, whereas co‐administration with ‐NAME, an eNOS inhibitor, further reduced EDD similarly in both groups. Endothelium‐independent dilatation to sodium nitroprusside (EID), was not altered by age or sirtinol treatment. In older (64 ± 1 years, = 22) . young (25 ± 1 years, = 16) healthy humans, ACh‐induced forearm EDD was impaired (= 0.01) and SIRT‐1 protein expression was 37% lower in endothelial cells obtained from the brachial artery ( 〈 0.05), whereas EID did not differ. In the overall group, EDD was positively related to endothelial cell SIRT‐1 protein expression (= 0.44, 〈 0.01). Reductions in SIRT‐1 may play an important role in vascular endothelial dysfunction with ageing. SIRT‐1 may be a key therapeutic target to treat arterial ageing.
    Keywords: Enzymes -- Physiological Aspects ; Nitroprusside -- Physiological Aspects ; Endothelium -- Physiological Aspects ; Nitric Oxide -- Physiological Aspects ; Acetylcholine -- Physiological Aspects ; Cyanides -- Physiological Aspects;
    ISSN: 0022-3751
    E-ISSN: 1469-7793
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  • 3
    In: Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 2011, Vol. 66A(4), pp.409-418
    Description: We hypothesized that I kappa B kinase (IKK)-mediated nuclear factor kappa B and forkhead BoxO3a phosphorylation will be associated with age-related endothelial dysfunction. Endothelium-dependent dilation and aortic protein expression/phosphorylation were determined in young and old male B6D2F1 mice and old mice treated with the IKK inhibitor, salicylate. IKK activation was greater in old mice and was associated with greater nitrotyrosine and cytokines. Endothelium-dependent dilation, nitric oxide (NO), and endothelial NO synthase phosphorylation were lower in old mice. Endothelium-dependent dilation and NO bioavailability were restored by a superoxide dismutase mimetic. Nuclear factor kappa B and forkhead BoxO3a phosphorylation were greater in old and were associated with increased expression/activity of nicotinamide adenine dinucleotide phosphate oxidase and lower manganese superoxide dismutase expression. Salicylate lowered IKK phosphorylation and reversed age-associated changes in nitrotyrosine, endothelium-dependent dilation, NO bioavailability, endothelial NO synthase, nuclear factor kappa B and forkhead BoxO3a phosphorylation, nicotinamide adenine dinucleotide phosphate oxidase, and manganese superoxide dismutase. Increased activation of IKK with advancing age stimulates nuclear factor kappa B and inactivates forkhead BoxO3a. This altered transcription factor activation contributes to a pro-inflammatory/pro-oxidative arterial phenotype that is characterized by increased cytokines and nicotinamide adenine dinucleotide phosphate oxidase and decreased manganese superoxide dismutase leading to oxidative stress-mediated endothelial dysfunction.
    Keywords: Edd ; Nadph Oxidase ; Sod
    ISSN: 1079-5006
    E-ISSN: 1758-535X
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  • 4
    In: Journal of Physiology, 15 October 2010, Vol.588(20), pp.3971-3982
    Description: We tested the hypothesis that carotid artery stiffening with ageing is associated with transforming growth factor‐β1 (TGF‐β1)‐related increases in adventitial collagen and reductions in medial elastin, which would be reversed by voluntary aerobic exercise. carotid artery incremental stiffness was greater in old (29–32 months, = 11) young (4–7 months, = 8) cage control B6D2F1 mice (8.84 ± 1.80 4.54 ± 1.18 AU, 〈 0.05), and was associated with selective increases in collagen I and III and TGF‐β1 protein expression in the adventitia ( 〈 0.05), related to an increase in smooth muscle α‐actin (SMαA) (myofibroblast phenotype) ( 〈 0.05). In cultured adventitial fibroblasts, TGF‐β1 induced increases in superoxide and collagen I protein ( 〈 0.05), which were inhibited by Tempol, a superoxide dismutase. Medial elastin was reduced with ageing, accompanied by decreases in the pro‐synthetic elastin enzyme, lysyl oxidase, and increases in the elastin‐degrading enzyme, matrix metalloproteinase 2. Fibronectin was unchanged with ageing, but there was a small increase in calcification ( 〈 0.05). Increased incremental stiffness in old mice was completely reversed (3.98 ± 0.34 AU, = 5) by 10–14 weeks of modest voluntary wheel running (1.13 ± 0.29 km day), whereas greater voluntary wheel running (10.62 ± 0.49 km day) had no effect on young mice. The amelioration of carotid artery stiffness by wheel running in old mice was associated with reductions in collagen I and III and TGF‐β1, partial reversal of the myofibroblast phenotype (reduced SMαA) and reduced calcification (all 〈 0.05 old controls), whereas elastin and its modulating enzymes were unaffected. Adventitial TGF‐β1‐related oxidative stress may play a key role in collagen deposition and large elastic artery stiffening with ageing and the efficacious effects of voluntary aerobic exercise. Advancing age causes large arteries in the chest and neck to stiffen, which increases the chances of having a heart attack or stroke. Arteries are composed of two main extracellular proteins, collagen and elastin, which contribute to both the structure and the stiffness of vessels. Regular exercise decreases the stiffening of arteries with ageing. However, the specific location of the changes in collagen and elastin within the arteries with ageing that lead to stiffening and the effects of exercise are unknown. Here we show that reduced stiffness in older mice that exercise is largely due to reductions in collagen in the adventitial (outermost) layer of arteries. However, exercise had no effect on elastin content. These results increase our understanding of how these large arteries stiffen with old age and the processes by which regular exercise helps to prevent this.
    Keywords: Aging -- Metabolism ; Carotid Artery Diseases -- Metabolism ; Collagen -- Metabolism ; Physical Conditioning, Animal -- Physiology ; Transforming Growth Factor Beta1 -- Metabolism;
    ISSN: 0022-3751
    E-ISSN: 1469-7793
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  • 5
    Language: English
    In: Journal of Physiology, Oct, 2010, Vol.588(20), p.3971(12)
    Description: To authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1113/jphysiol.2010.194753 Byline: Bradley S. Fleenor (1), Kurt D. Marshall (1), Jessica R. Durrant (1), Lisa A. Lesniewski (1), Douglas R. Seals (1) Abstract: We tested the hypothesis that carotid artery stiffening with ageing is associated with transforming growth factor-[beta]1 (TGF-[beta]1)-related increases in adventitial collagen and reductions in medial elastin, which would be reversed by voluntary aerobic exercise. Ex vivo carotid artery incremental stiffness was greater in old (29-32 months, n= 11) vs. young (4-7 months, n= 8) cage control B6D2F1 mice (8.84 [+ or -] 1.80 vs. 4.54 [+ or -] 1.18 AU, P 〈 0.05), and was associated with selective increases in collagen I and III and TGF-[beta]1 protein expression in the adventitia (P 〈 0.05), related to an increase in smooth muscle [alpha]-actin (SM[alpha]A) (myofibroblast phenotype) (P 〈 0.05). In cultured adventitial fibroblasts, TGF-[beta]1 induced increases in superoxide and collagen I protein (P 〈 0.05), which were inhibited by Tempol, a superoxide dismutase. Medial elastin was reduced with ageing, accompanied by decreases in the pro-synthetic elastin enzyme, lysyl oxidase, and increases in the elastin-degrading enzyme, matrix metalloproteinase 2. Fibronectin was unchanged with ageing, but there was a small increase in calcification (P 〈 0.05). Increased incremental stiffness in old mice was completely reversed (3.98 [+ or -] 0.34 AU, n= 5) by 10-14 weeks of modest voluntary wheel running (1.13 [+ or -] 0.29 km day.sup.-1), whereas greater voluntary wheel running (10.62 [+ or -] 0.49 km day.sup.-1) had no effect on young mice. The amelioration of carotid artery stiffness by wheel running in old mice was associated with reductions in collagen I and III and TGF-[beta]1, partial reversal of the myofibroblast phenotype (reduced SM[alpha]A) and reduced calcification (all P 〈 0.05 vs. old controls), whereas elastin and its modulating enzymes were unaffected. Adventitial TGF-[beta]1-related oxidative stress may play a key role in collagen deposition and large elastic artery stiffening with ageing and the efficacious effects of voluntary aerobic exercise. Author Affiliation: (1)Department of Integrative Physiology, University of Colorado, Boulder, CO 80309, USA Article History: (Received 14 June 2010; accepted after revision 23 August 2010; first published online 31 August 2010) Article note: Corresponding author B. S. Fleenor: University of Colorado, 354 UCB, Boulder, CO 80309, USA. Email: bradley.fleenor@colorado.edu
    Keywords: Actin -- Physiological Aspects ; Exercise -- Physiological Aspects ; Oxidases -- Physiological Aspects ; Transforming Growth Factors -- Physiological Aspects ; Fibronectins -- Physiological Aspects ; Superoxides -- Physiological Aspects ; Proteins -- Physiological Aspects
    ISSN: 0022-3751
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  • 6
    Language: English
    In: Veterinary Medicine, 2015, Vol.110(9), p.237(4)
    Keywords: Rabbits – Diseases ; Respiratory Tract Diseases – Diagnosis ; Respiratory Tract Diseases – Care and Treatment
    ISSN: 8750-7943
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  • 7
    Language: English
    In: American Journal of Physiology (Consolidated), 2011, Vol.301(3), p.H1025(8)
    Description: We tested the hypothesis that regular aerobic exercise reverses arterial inflammation with aging. When compared with young controls (6.2 [+ or -] 0.4 mo; n = 7), old (31.3 [+ or -] 0.5 mo; n = 11) male B6D2F1 cage-restricted mice demonstrated increased arterial activation of the proinflammatory transcription factor NF-[kappa]B, as indicated by greater aortic phosphorylation of both the inhibitor of NF-[kappa]B kinase (IKK) and the p65 subunit of NF-[kappa]B (both P 〈 0.05). Similarly, aortic expression of the proinflammatory cytokines IL-1 and IL-6, IFN-[gamma] and TNF-[alpha] were greater in the old mice (all P 〈 0.05). Macrophage and T lymphocyte abundance was unchanged with age in the aortic intima and media but was markedly increased in the adventitia and perivascular fat tissue of old mice (all P 〈 0.05). This proinflammatory arterial phenotype with aging was associated with vascular dysfunction, as reflected by impaired nitric oxide-mediated endothelium-dependent dilation. Voluntary wheel running (10-14 wk) normalized aortic IKK-NF-[kappa]B activation, cytokine expression, adventitial and perivascular macrophage infiltration, and vascular function in old mice (32.4 [+ or -] 0.3 mo; n = 8) while having no consistent effects in young mice. Short-term voluntary wheel running started late in life reverses arterial inflammation with aging in mice possibly via outside-in actions. These anti-inflammatory effects may play an important role in the amelioration of age-associated vascular dysfunction by regular aerobic exercise. nuclear factor-[kappa]B; cytokines; macrophages; vascular dysfunction doi: 10.1152/ajpheart.01276.2010
    Keywords: Aging (Biology) – Physiological Aspects ; Exercise – Physiological Aspects ; Inflammation – Development and Progression ; Inflammation – Genetic Aspects ; Inflammation – Research
    ISSN: 0002-9513
    Source: Cengage Learning, Inc.
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  • 8
    Language: English
    In: The American Journal of Physiology, Sept, 2011, Vol.301(3), p.H1025(8)
    Description: We tested the hypothesis that regular aerobic exercise reverses arterial inflammation with aging. When compared with young controls (6.2 [+ or -] 0.4 mo; n = 7), old (31.3 [+ or -] 0.5 mo; n = 11) male B6D2F1 cage-restricted mice demonstrated increased arterial activation of the proinflammatory transcription factor NF-[kappa]B, as indicated by greater aortic phosphorylation of both the inhibitor of NF-[kappa]B kinase (IKK) and the p65 subunit of NF-[kappa]B (both P 〈 0.05). Similarly, aortic expression of the proinflammatory cytokines IL-1 and IL-6, IFN-[gamma] and TNF-[alpha] were greater in the old mice (all P 〈 0.05). Macrophage and T lymphocyte abundance was unchanged with age in the aortic intima and media but was markedly increased in the adventitia and perivascular fat tissue of old mice (all P 〈 0.05). This proinflammatory arterial phenotype with aging was associated with vascular dysfunction, as reflected by impaired nitric oxide-mediated endothelium-dependent dilation. Voluntary wheel running (10-14 wk) normalized aortic IKK-NF-[kappa]B activation, cytokine expression, adventitial and perivascular macrophage infiltration, and vascular function in old mice (32.4 [+ or -] 0.3 mo; n = 8) while having no consistent effects in young mice. Short-term voluntary wheel running started late in life reverses arterial inflammation with aging in mice possibly via outside-in actions. These anti-inflammatory effects may play an important role in the amelioration of age-associated vascular dysfunction by regular aerobic exercise. nuclear factor-[kappa]B; cytokines; macrophages; vascular dysfunction doi: 10.1152/ajpheart.01276.2010
    Keywords: Aging (Biology) -- Physiological Aspects ; Exercise -- Physiological Aspects ; Inflammation -- Development And Progression ; Inflammation -- Genetic Aspects ; Inflammation -- Research
    ISSN: 0002-9513
    Source: Cengage Learning, Inc.
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  • 9
    Language: English
    In: Mechanisms of Ageing and Development, May 2012, Vol.133(5), pp.368-371
    Description: ► Aging is associated with decreased arterial AMPK expression. ► Short-term pharmacological AMPK activation with AICAR ameliorates age-associated vascular endothelial dysfunction by reducing oxidative stress. ► AMPK activation is a potential therapy for treating arterial aging and reducing cardiovascular disease risk. Exercise restores endothelium-dependent dilation (EDD) in old mice by reducing oxidative stress and increasing nitric oxide (NO) bioavailability. Adenosine monophosphate protein kinase (AMPK) activation mimics some effects of exercise. Old (28–30 months) B6D2F1 mice had reduced arterial AMPK expression and superoxide-mediated suppression of EDD vs. young (3–6 months) controls. Pharmacological activation of AMPK by aminoimidazole carboxamide ribonucleotide (AICAR) for 2 weeks increased arterial AMPK and reversed this superoxide-induced impairment of EDD. The improvement in EDD was independent of NO or prostaglandin signaling, suggesting enhanced endothelium-dependent hyperpolarizing factor-related dilation. AMPK activation may represent a novel therapy for treating age-associated vascular dysfunction.
    Keywords: Endothelium-Dependent Dilation ; Prostaglandins ; Endothelium-Dependent Hyperpolarizing Factor ; Medicine ; Anatomy & Physiology ; Zoology
    ISSN: 0047-6374
    E-ISSN: 1872-6216
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  • 10
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