Cilostazol Inhibits Oxidative Stress–Induced Premature Senescence Via Upregulation of Sirt1 in Human Endothelial Cells

Ota, Hidetaka; Eto, Masato; Kano, Mitsunobu R.; Ogawa, Sumito; Iijima, Katsuya; Akishita, Masahiro; Ouchi, Yasuyoshi

doi:10.1161/atvbaha.108.164368

Cited by 204 publications

(157 citation statements)

References 27 publications

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“…Cilostazol increased eNOS activity, expression of eNOS and the phosphorylation of eNOS at Ser 1177 in parallel with the phosphrylation of Akt at Ser 473 . These results suggest that the protective effect against a senescent phenotype may be attributable to an increase in NO via eNOS activation by cilostazol 25) . To explore the mechanism by which cilostazol prevents endothelial senescence, we considered that an increase in NO production could promote the longevity gene, SIRT1.…”

Section: Cilostazol Inhibits Oxidative Stress-induced Premature Senesmentioning

confidence: 75%

SIRT1/eNOS Axis as a Potential Target against Vascular Senescence, Dysfunction and Atherosclerosis

Ota¹,

Eto²,

Ogawa³

et al. 2010

JAT

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125

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Sir2 (silent information regulator-2), an NAD -dependent histone deacetylase, is highly conserved in organisms ranging from archaea to humans. Yeast Sir2 is responsible for silencing at repeated DNA sequences in mating-type loci, telomeres and rDNA, and plays critical roles in DNA repair, stress resistance and longevity. The phenomenon of human aging is known to be a critical cardiovascular risk factor. Senescence of endothelial cells has been proposed to be involved in vascular dysfunction and atherogenesis. Recent studies have demonstrated that mammalian Sirt1 NAD -dependent protein deacetylase, the closest homologue of Sir2, regulates vascular angiogenesis, homeostasis and senescence. This review focuses on SIRT1 as a potential therapeutic target against atherosclerosis.J Atheroscler Thromb, 2010; 17:431-435.

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Section: Cilostazol Inhibits Oxidative Stress-induced Premature Senesmentioning

confidence: 75%

SIRT1/eNOS Axis as a Potential Target against Vascular Senescence, Dysfunction and Atherosclerosis

Ota¹,

Eto²,

Ogawa³

et al. 2010

JAT

Self Cite

125

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“…SIRT1 deacetylates lysines at position K496 and K506 in the calmodulin-binding domain of endothelial nitric oxide synthase, leading to enhanced nitric oxide production, which is vital for endothelial-dependent vasorelaxation, cell survival, migration, and postnatal neovascularization (10,84). NO activates the SIRT1 promoter, thereby increasing SIRT1 mRNA and protein levels (100,105), suggesting that a positive feedback mechanism exists between SIRT1 and endothelial nitric oxide synthase (110). Therefore, the activation of SIRT1 by small molecules (such as SRT1720) may help in resetting the endothelial nitric oxide synthase activity during endothelial dysfunction in patients with COPD, where NO availability is limited (87).…”

Section: Fig 6 Role Of Sirt1 Foxo3mentioning

confidence: 99%

Oxidative Stress and Chromatin Remodeling in Chronic Obstructive Pulmonary Disease and Smoking-Related Diseases

Sundar

Yao

Rahman

2013

Antioxidants & Redox Signaling

157

104

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Significance: Chronic obstructive pulmonary disease (COPD) is predominantly a tobacco smoke-triggered disease with features of chronic low-grade systemic inflammation and aging (inflammaging) of the lung associated with steroid resistance induced by cigarette smoke (CS)-mediated oxidative stress. Oxidative stress induces various kinase signaling pathways leading to chromatin modifications (histone acetylation/deacetylation and histone methylation/demethylation) in inflammation, senescence, and steroid resistance. Recent Advances: Histone mono-, di-, or tri-methylation at lysine residues result in either gene activation (H3K4, H3K36, and H3K79) or repression (H3K9, H3K27, and H3K20). Cross-talk occurs between various epigenetic marks on histones and DNA methylation. Both CS and oxidants alter histone acetylation/deacetylation and methylation/ demethylation leading to enhanced proinflammatory gene expression. Chromatin modifications occur in lungs of patients with COPD. Histone deacetylase 2 (HDAC2) reduction (levels and activity) is associated with steroid resistance in response to oxidative stress. Critical Issues: Histone modifications are associated with DNA damage/repair and epigenomic instability as well as premature lung aging, which have implications in the pathogenesis of COPD. HDAC2/SIRTUIN1 (SIRT1)-dependent chromatin modifications are associated with DNA damage-induced inflammation and senescence in response to CS-mediated oxidative stress. Future Directions: Understanding CS/oxidative stress-mediated chromatin modifications and the cross-talk between histone acetylation and methylation will demonstrate the involvement of epigenetic regulation of chromatin remodeling in inflammaging. This will lead to identification of novel epigenetic-based therapies against COPD and other smoking-related lung diseases. Pharmacological activation of HDAC2/SIRT1 or reversal of their oxidative post-translational modifications may offer therapies for treatment of COPD and CS-related diseases based on epigenetic histone modifications.

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“…Senescent vascular endothelial cells have been observed in the atherosclerotic plaques of human coronary arteries 6) which may suggest a relationship between aging of these cells and atherosclerosis. The senescence of endothelial cells is induced by oxidative stress and shear stress [6][7][8] and promotes inflammation and atherosclerosis. 7) However, it is unclear if replicative senescence (i.e., ''pure'' senescence) contributes to the pathogenesis of atherosclerosis.…”

mentioning

confidence: 99%

“…The senescence of endothelial cells is induced by oxidative stress and shear stress [6][7][8] and promotes inflammation and atherosclerosis. 7) However, it is unclear if replicative senescence (i.e., ''pure'' senescence) contributes to the pathogenesis of atherosclerosis.…”

mentioning

confidence: 99%

Increased Monocytic Adhesion by Senescence in Human Umbilical Vein Endothelial Cells

Yanaka

Honma

Sato

et al. 2011

Bioscience, Biotechnology, and Biochemistry

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Cilostazol Inhibits Oxidative Stress–Induced Premature Senescence Via Upregulation of Sirt1 in Human Endothelial Cells

Cited by 204 publications

References 27 publications

SIRT1/eNOS Axis as a Potential Target against Vascular Senescence, Dysfunction and Atherosclerosis

SIRT1/eNOS Axis as a Potential Target against Vascular Senescence, Dysfunction and Atherosclerosis

Oxidative Stress and Chromatin Remodeling in Chronic Obstructive Pulmonary Disease and Smoking-Related Diseases

Increased Monocytic Adhesion by Senescence in Human Umbilical Vein Endothelial Cells

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