Increased Blood Plasminogen Activator Inhibitor-1 and Intercellular Adhesion Molecule-1 as Possible Risk Factors of Atherosclerosis in Werner Syndrome

Murano, Shunichi; Nakazawa, Atsumi; Masuda, Minoru; Morisaki, Naho; Akikusa, Bunshiro; Tsuboyama, Tadao; Saitō, Yasushi

doi:10.1159/000213885

Cited by 18 publications

(15 citation statements)

References 16 publications

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“…Previous studies show that WS fibroblasts express inflammatory cytokines [38] and WS is associated with inflammatory conditions such as atherosclerosis, diabetes and osteoporosis [39]–[43]. The present data indicate that both CDKI and SASP genes are prematurely induced in WS fibroblasts compared with PDL-matched normal fibroblasts.…”

Section: Discussionsupporting

confidence: 63%

Reprogramming Suppresses Premature Senescence Phenotypes of Werner Syndrome Cells and Maintains Chromosomal Stability over Long-Term Culture

et al. 2014

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Werner syndrome (WS) is a premature aging disorder characterized by chromosomal instability and cancer predisposition. Mutations in WRN are responsible for the disease and cause telomere dysfunction, resulting in accelerated aging. Recent studies have revealed that cells from WS patients can be successfully reprogrammed into induced pluripotent stem cells (iPSCs). In the present study, we describe the effects of long-term culture on WS iPSCs, which acquired and maintained infinite proliferative potential for self-renewal over 2 years. After long-term cultures, WS iPSCs exhibited stable undifferentiated states and differentiation capacity, and premature upregulation of senescence-associated genes in WS cells was completely suppressed in WS iPSCs despite WRN deficiency. WS iPSCs also showed recapitulation of the phenotypes during differentiation. Furthermore, karyotype analysis indicated that WS iPSCs were stable, and half of the descendant clones had chromosomal profiles that were similar to those of parental cells. These unexpected properties might be achieved by induced expression of endogenous telomerase gene during reprogramming, which trigger telomerase reactivation leading to suppression of both replicative senescence and telomere dysfunction in WS cells. These findings demonstrated that reprogramming suppressed premature senescence phenotypes in WS cells and WS iPSCs could lead to chromosomal stability over the long term. WS iPSCs will provide opportunities to identify affected lineages in WS and to develop a new strategy for the treatment of WS.

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Section: Discussionsupporting

confidence: 63%

Reprogramming Suppresses Premature Senescence Phenotypes of Werner Syndrome Cells and Maintains Chromosomal Stability over Long-Term Culture

et al. 2014

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“…Additionally, WRN regulates expression of PAI-1 [59]. Consistent with this, PAI-1 levels are elevated in WS cells [60], which may correlate with occurrence of artherosclerosis in WS. More work is needed in this area to detect associations between WRN SNPs and aspects of the aging phenotype.…”

Section: Molecular Genetics Of Werner Syndrome (Ws)mentioning

confidence: 83%

Roles of Werner syndrome protein in protection of genome integrity

2010

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OverviewWerner syndrome protein (WRN) is one of a family of five human RecQ helicases implicated in the maintenance of genome stability. The conserved RecQ family also includes RecQ1, Bloom syndrome protein (BLM), RecQ4, and RecQ5 in humans (see additional reviews in this issue), as well as Sgs1 in Saccharomyces cerevisiae, Rqh1 in Schizosaccharomyces pombe, and homologs in Caenorhabditis elegans, Xenopus laevis, and Drosophila melanogaster [1]. Defects in three of the RecQ helicases, RecQ4, BLM, and WRN, cause human pathologies linked with cancer predisposition and premature aging [1][2][3][4][5]. Mutations in the WRN gene are the causative factor of Werner syndrome (WS). WRN is one of the best characterized of the RecQ helicases and is known to have roles in DNA replication and repair, transcription, and telomere maintenance [1][2][3][4][5][6]. Studies both in vitro and in vivo indicate that the roles of WRN in a variety of DNA processes are mediated by post-translational modifications, as well as several important protein-protein interactions [1,2,7]. Many of these functions of WRN in genome maintenance, as well as the clinical characteristics of WS, have been recently reviewed [8][9][10][11][12]. In this work, we will summarize some of the early studies on the cellular roles of WRN and highlight the recent findings that shed some light on the link between the protein and its cellular functions with the disease pathology. Molecular Genetics of Werner Syndrome (WS)WS is a rare autosomal recessive progeroid disorder characterized by the development of cataracts, changing of skin conditions, bird-like facies, atypical short stature, and premature graying or thinning of the hair [9]. Patients also often develop hypogonadism, osteoporosis, diabetes mellitus, artherosclerosis [13], and cancers, particularly sarcomas [14]. Onset of symptoms usually occurs in the third decade of life, and health subsequently declines with median age at death between 47-54 years [13]. Because WS presents with early-onset of conditions commonly seen in the aged, it is a good model system for the study of mechanisms of normal aging [15,16]. WRN BiochemistryThe causative factor of the majority of WS is mutation in the WRN gene, which codes for a member of the highly conserved RecQ family of helicases. While several different mutations within the gene are seen in WS, most result in production of truncated WRN protein [13]. 1Address correspondence to: Dr. Vilhelm A. Bohr, NIH Biomedical Research Center, 251 Bayview Boulevard, Baltimore, MD 21224; BohrV@grc.nia.nih.gov. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the...

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“…Fibroblasts derived from individuals with WS display activation of inflammatory signaling pathways and WS individuals exhibit high plasma levels of inflammatory cytokines [51,69] and ICAM-1 [70]. In addition, WS individuals have elevated levels of inflammatory diseases [5].…”

Section: Premature Ageing Disorders and Werner Syndromementioning

confidence: 99%

Use of p38 MAPK Inhibitors for the Treatment of Werner Syndrome

et al. 2010

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Werner syndrome provides a convincing model for aspects of the normal ageing phenotype and may provide a suitable model for therapeutic interventions designed to combat the ageing process. Cultured primary fibroblast cells from Werner syndrome patients provide a powerful model system to study the link between replicative senescence in vitro and in vivo pathophysiology. Genome instability, together with an increased pro-oxidant state, and frequent replication fork stalling, all provide plausible triggers for intracellular stress in Werner syndrome cells, and implicates p38 MAPK signaling in their shortened replicative lifespan. A number of different p38 MAPK inhibitor chemotypes have been prepared rapidly and efficiently using microwave heating techniques for biological study in Werner syndrome cells, including SB203580, VX-745, RO3201195, UR-13756 and BIRB 796, and their selectivity and potency evaluated in this cellular context. Werner syndrome fibroblasts treated with a p38 MAPK inhibitor reveal an unexpected reversal of the accelerated ageing phenotype. Thus the study of p38 inhibition and its effect upon Werner pathophysiology is likely to provide new revelations into the biological mechanisms operating in cellular senescence and human ageing in the future.

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Increased Blood Plasminogen Activator Inhibitor-1 and Intercellular Adhesion Molecule-1 as Possible Risk Factors of Atherosclerosis in Werner Syndrome

Cited by 18 publications

References 16 publications

Reprogramming Suppresses Premature Senescence Phenotypes of Werner Syndrome Cells and Maintains Chromosomal Stability over Long-Term Culture

Reprogramming Suppresses Premature Senescence Phenotypes of Werner Syndrome Cells and Maintains Chromosomal Stability over Long-Term Culture

Roles of Werner syndrome protein in protection of genome integrity

Use of p38 MAPK Inhibitors for the Treatment of Werner Syndrome

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