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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Werner syndrome (WS) is an uncommon autosomal recessive disorder characterized by premature aging. The clinical manifestations of WS, including atherosclerosis and osteoporosis, appear early in adulthood, and death in the fourth to sixth decade commonly ensues from myocardial infarction or cancer. In accord with the aging phenotype, cells from WS patients have a reduced replicative life span in culture. Genomic instability is observed at the cytogenetic level in the form of chromosome breaks and translocations and at the molecular level by multiple large deletions. The Werner syndrome gene (WRN) has recently been cloned. The predicted product is a 1,432-amino-acid protein whose central domain is homologous to members of the RecQ family of DNA helicases. Such homology does not necessarily mean that WRN encodes an active helicase. For example, the Saccharomyces cerevisiae RAD26 gene protein and the human transcription-repair coupling factor CSB (Cockayne syndrome 8) are highly homologous to known helicases, yet neither encodes an active helicase. Moreover, the Bloom's syndrome gene (BLM), discovered before WRN, is also homologous to the RecQ family of DNA helicases, though we still await demonstration that it encodes an active helicase. Here we report that the WS protein does indeed catalyze DNA unwinding.
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PMID:The Werner syndrome protein is a DNA helicase. 928 7

Werner syndrome (WS) is an autosomal recessive genetic disorder that is manifested by genetic instability and premature onset of age-related diseases, including atherosclerosis and cancer. The gene that is mutated in WS cells (WRN) has been identified recently. Characterizations of the WRN gene product indicate that WRN encodes both a 3'-->5' DNA helicase, belonging to the Escherichiacoli RecQ helicase family, and a 3'-->5' DNA exonuclease. Studies to define the molecular mechanism of WRN-DNA transactions are currently underway in many laboratories. Preliminary results indicate that WRN functions as a key factor in resolving aberrant DNA structures that arise from DNA metabolic processes such as replication, recombination and/or repair, to preserve the genetic integrity in cells.
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PMID:The Werner syndrome gene: the molecular basis of RecQ helicase-deficiency diseases. 1078 15

Although philosophers and scientists have long been interested in the aging process, general interest in this fascinating and highly important topic was minimal before the 1960s. In recent decades, however, interest in aging has greatly accelerated, not only since the elderly form an ever-increasing percentage of the population, but because they utilize a significant proportion of the national expenditures. In addition, many people have come to the realization that one can now lead a very happy, active, and productive life well beyond the usual retirement age. Scientifically, aging is an extremely complex, multifactorial process, and numerous aging theories have been proposed; the most important of these are probably the genomic and free radical theories. Although it is abundantly clear that our genes influence aging and longevity, exactly how this takes place on a chemical level is only partially understood. For example, what kinds of genes are these, and what proteins do they control? Certainly they include, among others, those that regulate the processes of somatic maintenance and repair, such as the stress-response systems. The accelerated aging syndromes (i.e., Hutchinson-Gilford, Werner's, and Down's syndromes) are genetically controlled, and studies of them have decidedly increased our understanding of aging. In addition, C. elegans and D. melanogaster are important systems for studying aging. This is especially true for the former, in which the age-1 mutant has been shown to greatly increase the life span over the wild-type strain. This genetic mutation results in increased activities of the antioxidative enzymes, Cu-Zn superoxide dismutase and catalase. Thus, the genomic and free radical theories are closely linked. In addition, trisomy 21 (Down's syndrome) is characterized by a significantly shortened life span; it is also plagued by increased oxidative stress which results in various free radical-related disturbances. Exactly how this extra chromosome results in an increased production of reactive oxygen species is, however, only partially understood. There is considerable additional indirect evidence supporting the free radical theory of aging. Not only are several major age-associated diseases clearly affected by increased oxidative stress (atherosclerosis, cancer, etc.), but the fact that there are numerous natural protective mechanisms to prevent oxyradical-induced cellular damage speaks loudly that this theory has a key role in aging [the presence of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, among others; various important intrinsic (uric acid, bilirubin, -SH proteins, glutathione, etc.) and extrinsic (vitamins C, E, carotenoids, flavonoids, etc.) antioxidants; and metal chelating proteins to prevent Fenton and Haber-Weiss chemistry]. In addition, a major part of the free radical theory involves the damaging role of reactive oxygen species and various toxins on mitochondria. These lead to numerous mitochondrial DNA mutations which result in a progressive reduction in energy output, significantly below that needed in body tissues. This can result in various signs of aging, such as loss of memory, hearing, vision, and stamina. Oxidative stress also inactivates critical enzymes and other proteins. In addition to these factors, caloric restriction is the only known method that increases the life span of rodents; studies currently underway suggest that this also applies to primates, and presumably to humans. Certainly, oxidative stress plays an important role here, although other, as yet unknown, factors are also presumably involved. Exactly how the other major theories (i.e., immune, neuroendocrine, somatic mutation, error catastrophe) control aging is more difficult to define. The immune and neuroendocrine systems clearly deteriorate with age. (ABSTRACT TRUNCATED)
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PMID:The biochemistry of aging. 1104 Sep 57

Werner's syndrome (WS), a representative progeroid syndrome with chromosomal instability caused by the mutation of RecQ type DNA/RNA helicase, manifests skin changes similar to those observed in systemic sclerosis (SSc). In addition, patients with WS show a variety of the signs and symptoms of normal ageing at an early stage of their life; gray hair, alopecia, muscle atrophy, osteoporosis, cataracts, hypogonadism, diabetes mellitus, hyperlipidemia, atherosclerosis, malignancy, brain atrophy, and senile dementia. Although no direct evidence has been presented linking RecQ type DNA/RNA helicase dysfunction with the occurrence of premature ageing symptoms in WS, WS may give us a unique model to analyze the skin changes and the mechanisms of fibrosis in SSc.
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PMID:Werner's syndrome: from clinics to genetics. 1113 45

Werner syndrome (WS) is a progeroid syndrome caused by autosomal recessive null mutations at the WRN locus. The WRN gene encodes a nuclear protein of 180 kD that contains both exonuclease and helicase domains. WS patients develop various forms of arteriosclerosis, particularly atherosclerosis, and medial calcinosis. The most common cause of death in Caucasian subjects with WS is myocardial infarction. Previous studies have identified specific polymorphisms within WRN that may modulate the risk of atherosclerosis. Population studies of the 1074Leu/Phe and 1367Cys/Arg polymorphisms were undertaken to evaluate the role of WRN in atherogenesis. Frequencies of the 1074Leu/Phe polymorphisms in Finnish and Mexican populations revealed an age-dependent decline of 1074Phe/Phe genotype. In Mexican newborns, but not in Finnish newborns, the 1074Leu/Phe and 1367Cys/ Arg polymorphisms were in linkage disequilibrium. Among coronary artery disease subjects, there was a tendency for the 1074Phe allele to be associated with coronary stenosis in a gene dose-dependent manner. Furthermore, the 1367Arg/Arg genotype predicted a lower degree of coronary artery occlusion, as measured by NV50, when compared to the 1367Cys/Cys or 1367Cys/Arg genotypes. However, these tendencies did not achieve statistical significance. Samples from Mexican patients with ischemic stroke showed a trend of haplotype frequencies different from that in a control group of Mexican adults. These data support the hypothesis that WRN may mediate not only WS, but may also modulate more common age-related disorders and, perhaps, a basic aging process.
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PMID:Polymorphisms at the Werner locus: II. 1074Leu/Phe, 1367Cys/Arg, longevity, and atherosclerosis. 1118 93

Atherosclerosis constitutes the most common medical and surgical problem. This can be manifested clinically as stroke, coronary artery disease, or peripheral vascular disease. In the present review the microscopic appearance of the normal arterial wall, the definition of atherosclerosis and the five theories of atherogenesis are described. These are: the lipid theory, the hemodynamic theory, the fibrin incrustation theory, the nonspecific mesenchymal hypothesis and the response to injury hypothesis. Based on the above theories the sequence of events in atherogenesis is analyzed. The classification of the atherosclerotic lesions according to Stary (types I-VI) and their characteristics appear in a table. The epidemiology and the role of the following risk factors are presented in detail: age, sex, lipid abnormalities, cigarette smoking, hypertension, diabetes mellitus, physical inactivity, alcohol consumption, obesity, and hemostatic factors. In addition, less common genetically determined associations like homocystinuria, Tangier disease, Hutchinson-Gilford syndrome (progeria), Werner's syndrome, radiation induced atherosclerosis and the implications of Chlamydia pneumoniae on the arterial wall are discussed.
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PMID:The genesis of atherosclerosis and risk factors: a review. 1122 92

Werner syndrome (WS) is an autosomal recessive disease manifested by the premature onset of age-related phenotypes, including diseases such as atherosclerosis and cancer. This mimicry of normal aging with the possible exception of central nervous system manifestations has made it a focus of recent molecular studies on the pathophysiology of aging. In culture, cells obtained from patients with WS are genetically unstable, characterized by an increased frequency of nonclonal translocations and extensive DNA deletions. The WS gene product (WRN) is a DNA helicase belonging to the RecQ family, but is unique within this family in that it also contains an exonuclease activity. In addition to unwinding double-stranded DNA, WRN helicase is able to resolve aberrant DNA structures such as G4 tetraplexes, triplexes and 4-way junctions. Concordant with this structure-specificity, WRN exonuclease preferentially hydrolyzes alternative DNA that contains bubbles, extra-helical loops, 3-way junctions or 4-way junctions. WRN has been shown to bind to and/or functionally interact with other proteins, including replication protein A (RPA), proliferating cell nuclear antigen (PCNA), DNA topoisomerase I, Ku 86/70, DNA polymerase delta and p53. Each of these interacting proteins is involved in DNA transactions including those that resolve alternative DNA structures or repair DNA damage. The biochemical activities of WRN and the functions of WRN associated proteins suggest that in vivo WRN resolves DNA topological or structural aberrations that either occur during DNA metabolic processes such as recombination, replication and repair, or are the outcome of DNA damage.
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PMID:Unwinding the molecular basis of the Werner syndrome. 1134 59

A number of mouse models have been identified and are being used for aging and age-associated disease research. However, the use of the genetically manipulated mouse model is still a relatively untapped resource for the study of the biology of aging. Genetically altered mice can be powerful tools for biology of aging research because gene expression can be controlled and correlated with established biomarkers. Standard transgene overexpression and gene targeting techniques were modified and used to generate 30 mouse lines during a 4-year period. These lines include models of Werner's syndrome (premature aging or progeria), Alzheimer's disease, other neurodegenerative condition, atherosclerosis, diabetes, immune dysfunction, musculoskeletal disorders, and oxidative stress. These new mouse models are providing additional insights into aging processes and will be useful for developing intervention strategies and collaborative interactions.
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PMID:Generation of genetically altered mouse models for aging studies. 1178 22

The RecQ family of DNA helicases have potential roles in DNA repair, replication and/or recombination pathways. In humans, a defect in the RecQ family helicases encoded by the BLM, WRN and RECQ4 genes gives rise to Bloom's (BS), Werner's (WS) and Rothmund-Thomson (RTS) syndromes, respectively. These disorders are associated with cancer predisposition and/or premature aging. In Bloom's syndrome, affected individuals are predisposed to many types of cancer at an early age. Werner's syndrome is a premature aging disorder with a complex phenotype, which includes many age-related disorders that develop from puberty, including greying and thinning of the hair, bilateral cataract formation, type II diabetes mellitus, osteoporosis and atherosclerosis. The phenotype of Rothmund-Thomson syndrome patients also consists of some features associated with premature aging, as well as predispositon to certain cancers. Here, we discuss the molecular basis of these RecQ helicase-deficient disorders.
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PMID:Premature aging in RecQ helicase-deficient human syndromes. 1220 42

Werner's syndrome or progeria, described for the first time in 1886, is a rare disease with autosomal recessive transmission, characterized by premature ageing of connective tissues. About 200 cases have since been reported in the literature. Most patients die young, generally from heart failure due to early coronary atherosclerosis [1]. The authors report the case of a 46-year-old woman presenting with cardiovascular abnormalities, unusual for her age, associated with a particular morphotype belonging to Werner's syndrome.
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PMID:[Werner's disease presenting as ischemic mitral incompetence]. 1255 82


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