Cigarette Smoke Induces Cellular Senescence via Werner's Syndrome Protein Down-regulation

Nyunoya, Toru; Monick, Martha M.; Klingelhutz, Aloysius J.; Glaser, Heather; Cagley, Jeffrey R.; Brown, Charles O.; Matsumoto, Eiyu; Aykin-Burns, Nūkhet; Spitz, Douglas R.; Oshima, Junko; Hunninghake, Gary W.

doi:10.1164/rccm.200802-320oc

Cited by 71 publications

(53 citation statements)

References 51 publications

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“…In contrast, p16 expression was higher in cells from patients with COPD than in those from controls, suggesting a major role for p16 in driving premature senescence in COPD. Indeed, p16 activation by nontelomeric signals such as oxidative stress leads to premature senescence, 17 but it also may occur during replicative senescence as a second barrier to cell proliferation. 8 In accordance with this possibility, we found a strong inverse relationship between PDL and the amount of p16 measured in passage 2 cells, as well as a relationship with telomere length.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary Artery Smooth Muscle Cell Senescence Is a Pathogenic Mechanism for Pulmonary Hypertension in Chronic Lung Disease

Noureddine

Gary-Bobo

Alifano

et al. 2011

Circulation Research

128

138

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Rationale: Senescence of pulmonary artery smooth muscle cells (PA-SMCs) caused by telomere shortening or oxidative stress may contribute to pulmonary hypertension associated with chronic lung diseases.Objective: To investigate whether cell senescence contributes to pulmonary vessel remodeling and pulmonary hypertension in chronic obstructive pulmonary disease (COPD). Methods and Results:In 124 patients with COPD investigated by right heart catheterization, we found a negative correlation between leukocyte telomere length and pulmonary hypertension severity. In-depth investigations of lung vessels and derived cultured PA-SMCs showed greater severity of remodeling and increases in senescent p16-positive and p21-positive PA-SMCs and proliferating Ki67-stained cells in 14 patients with COPD compared to 13 age-matched and sex-matched control subjects who smoke. Cultured PA-SMCs from COPD patients displayed accelerated senescence, with fewer cell population doublings, an increased percentage of ␤-galactosidase-positive cells, shorter telomeres, and higher p16 protein levels at an early cell passage compared to PA-SMCs from controls. Both in situ and in vitro PA-SMC senescence criteria correlated closely with the degree of pulmonary vessel wall hypertrophy. Because senescent PA-SMCs stained for p16 and p21 were virtually confined to the media near the Ki67-positive cells, which predominated in the neointima and hypertrophied media, we evaluated whether senescent cells affected normal PA-SMC functions. We found that senescent PA-SMCs stimulated the growth and migration of normal target PA-SMCs through the production and release of paracrine soluble and insoluble factors. Conclusion

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Section: Discussionmentioning

confidence: 99%

Pulmonary Artery Smooth Muscle Cell Senescence Is a Pathogenic Mechanism for Pulmonary Hypertension in Chronic Lung Disease

Noureddine

Gary-Bobo

Alifano

et al. 2011

Circulation Research

128

138

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“…Senescence has also recently been implicated in developmental processes during tissue damage, as well as in ageing [27]. Evidence from clinical samples and mouse models demonstrates the induction of senescence in lung parenchymal cells in the progress of COPD and in response to cigarette smoke [52,[97][98][99][100]. Senescence of endothelial cells has also been linked to the pathomechanism of COPD and correlates with telomere dysfunction in these patients [50].…”

Section: Cellular Senescencementioning

confidence: 99%

“…Some patients with hereditary defects in DNA repair genes, such as in Werner progeria syndrome, develop primary lung cancers [133]. NYUNOYA et al [99] showed that cigarette smoke impairs expression of Werner's syndrome protein, a RecQ helicase involved in DNA repair, which is associated with cellular senescence in lung fibroblasts and epithelial cells. Genetic variations such as single nucleotide polymorphisms (SNPs) in DNA repair genes are predictive for lung cancer progression [134,135].…”

Section: Genomic Instabilitymentioning

confidence: 99%

Hallmarks of the ageing lung

2015

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Ageing is the main risk factor for major non-communicable chronic lung diseases, including chronic obstructive pulmonary disease, most forms of lung cancer and idiopathic pulmonary fibrosis. While the prevalence of these diseases continually increases with age, their respective incidence peaks at different times during the lifespan, suggesting specific effects of ageing on the onset and/or pathogenesis of chronic obstructive pulmonary disease, lung cancer and idiopathic pulmonary fibrosis. Recently, the nine hallmarks of ageing have been defined as cell-autonomous and non-autonomous pathways involved in ageing. Here, we review the available evidence for the involvement of each of these hallmarks in the pathogenesis of chronic obstructive pulmonary disease, lung cancer, or idiopathic pulmonary fibrosis. Importantly, we propose an additional hallmark, "dysregulation of the extracellular matrix", which we argue acts as a crucial modifier of cell-autonomous changes and functions, and as a key feature of the above-mentioned lung diseases. @ERSpublications Hallmarks of ageing are selecting factors for the pathogenesis of COPD, lung cancer and IPF

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“…For example, smoking increases arterial stiffness and pulse pressure 121 and promotes SIPS in ECs and fibroblasts. 1,122 Similarly, whereas low to moderate and/or acute alcohol intake are associated with reduced arterial stiffness, chronic higher alcohol intake (Ͼ21 U/wk) results in opposing effects. 123,124 Finally, ageand diet-associated elevation of serum glucose is associated with both premature vascular stiffness and vascular cell senescence, which are particularly pronounced in younger patients 125 and can be reduced by physiological levels of insulin.…”

Section: Systemic Causesmentioning

confidence: 99%

Aging and Atherosclerosis

Wang

Bennett

2012

Circulation Research

745

323

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Atherosclerosis is classed as a disease of aging, such that increasing age is an independent risk factor for the development of atherosclerosis. Atherosclerosis is also associated with premature biological aging, as atherosclerotic plaques show evidence of cellular senescence characterized by reduced cell proliferation, irreversible growth arrest and apoptosis, elevated DNA damage, epigenetic modifications, and telomere shortening and dysfunction. Not only is cellular senescence associated with atherosclerosis, there is growing evidence that cellular senescence promotes atherosclerosis. This review examines the pathology of normal vascular aging, the evidence for cellular senescence in atherosclerosis, the mechanisms underlying cellular senescence including reactive oxygen species, replication exhaustion and DNA damage, the functional consequences of vascular cell senescence, and the possibility that preventing accelerated cellular senescence is a therapeutic target in atherosclerosis.

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Cigarette Smoke Induces Cellular Senescence via Werner's Syndrome Protein Down-regulation

Cited by 71 publications

References 51 publications

Pulmonary Artery Smooth Muscle Cell Senescence Is a Pathogenic Mechanism for Pulmonary Hypertension in Chronic Lung Disease

Pulmonary Artery Smooth Muscle Cell Senescence Is a Pathogenic Mechanism for Pulmonary Hypertension in Chronic Lung Disease

Hallmarks of the ageing lung

Aging and Atherosclerosis

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