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

An integrative theory is proposed in which environmental carcinogenesis is viewed as a process by which the genetic control of cell division and differentiation is altered by carcinogens. In this theory, carcinogens include physical, chemical, and viral "mutagens," as well as chemical and viral gene modulators. Existing explanations of carcinogenesis can be considered either as somatic mutation theories or as epigenetic theories. Evidence seems to support the hypothesis that both mutations and epigenetic processes are components of carcinogenesis. The mutational basis of cancer is supported by the clonal nature of tumors, the mutagenicity of most carcinogens, high mutation frequencies in cells of cancer-prone human fibroblasts lacking DNA repair enzymes, the correlation of in vitro DNA damage and in vitro mutation and transformation frequencies with in vivo tumorigenesis, age-related incidences of various hereditary tumors, and the correlation between photoreactivation of DNA damage and the biological amelioration of UV-induced neoplasms. Since both mutagens and gene modulators can be carcinogenic it may be that carcinogens affect genes which control cell division. An integration of the mutation and epigenetic theories of cancer with the "two-stage" theory and Comings's general theory of carcinogenesis is proposed. This integrative theory postulates that carcinogens can affect regulatory genes which control a series of "transforming genes." A general hypothesis is advanced that involves a common mechanism of somatic mutagenesis via error-prone repair of DNA damage which links carcinogenesis, teratogenesis, atherosclerosis and aging. Various concepts are presented to provide a framework for evaluating the scientific, medical, and social implications of cancer.
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PMID:Environmental carcinogenesis: an integrative model. 36 70

Oxidative stress is strongly implicated in a number of diseases, such as rheumatoid arthritis, inflammatory bowel disorders, and atherosclerosis, and its emerging as one of the most important causative agents of mutagenesis, tumorigenesis, and aging. Recent progress on the genetics and molecular biology of the cellular responses to oxidative stress, primarily in Escherichia coli and Salmonella typhimurium, is summarized. Bacteria respond to oxidative stress by invoking two distinct stress responses, the peroxide stimulon and the superoxide stimulon, depending on whether the stress is mediated by peroxides or the superoxide anion. The two stimulons each contain a set of more than 30 genes. The expression of a subset of genes in each stimulon is under the control of a positive regulatory element; these genes constitute the OxyR and SoxRS regulons. The schemes of regulation of the two regulons by their respective regulators are reviewed in detail, and the overlaps of these regulons with other stress responses such as the heat shock and SOS responses are discussed. The products of Oxy-R- and SoxRS-regulated genes, such as catalases and superoxide dismutases, are involved in the prevention of oxidative damage, whereas others, such as endonuclease IV, play a role in the repair of oxidative damage. The potential roles of these and other gene products in the defense against oxidative damage in DNA, proteins, and membranes are discussed in detail. A brief discussion of the similarities and differences between oxidative stress responses in bacteria and eukaryotic organisms concludes this review.
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PMID:Oxidative stress responses in Escherichia coli and Salmonella typhimurium. 177 27

Platelets participate in the pathogenesis of arteriosclerosis and in the progression of atherosclerosis by adhering to the damaged arteries and subsequently forming mural thrombi which are either swept away and embolize or are endothelialized and thus become part of the vessel wall. Rheologic considerations predict and blood perfusion experiments using flow chambers with exposed vessel wall components demonstrate that platelet participation increases with the wall shear rate and is thus particularly important in stenosed arteries (acute thrombosis) and the microvasculature (hemostasis). In addition to their involvement in thrombosis, activated platelets release growth factors, most notably a platelet-derived growth factor (PDGF) which may be the principal mediator of smooth muscle cell migration from the media into the intima and of smooth muscle cell proliferation in the intima as well as of vasoconstriction. The recent discovery that PDGF can be produced by additional cells involved in the pathogenesis of arteriosclerosis (endothelial cells, monocytes/macrophages, smooth muscle cells themselves) and that they may play a role in tumorigenesis has tremendously increased the interest in this growth factor and in potential antagonists.
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PMID:Platelets, platelet-derived growth factor and arteriosclerosis. 327 18

Human atherosclerotic fibrous plaques display a clonal character similar to many benign neoplasms. We report here that chickens treated with an initiation-promotion sequence developed focal intimal smooth muscle lesions in the thoracic aorta that resemble early forms of atherosclerosis. Scanning electron microscopy revealed small mound-like lesions protruding from an intact endothelium in birds treated with an initiating dose of 7,12-dimethylbenz[a]anthracene (Me2BA) followed by twice weekly injections of the alpha 1-selective adrenergic agonist methoxamine for 20 weeks. Intimal lesion foci were composed of densely packed modified smooth muscle cells, abundant extracellular matrix, and occasional mononuclear cells (possibly monocytes). There was no ultrastructural evidence of lipid accumulation or alteration of the underlying media. These intimal lesions appeared in aortic segments of treated chickens in a pattern similar to that observed in classical experiments of multistage tumorigenesis in epidermis and other tissues. The treatment with Me2BA followed by methoxamine produced more focal lesions per thoracic segment and more segments per group with lesions than did treatment with either Me2BA or methoxamine alone. Thoracic intimal foci were absent from untreated and vehicle-treated groups. In contrast, the growth of a spontaneously arising atheroma in the distal abdominal aorta was not demonstrably affected by the initiation-promotion regimen. Likewise, weekly injections of Me2BA for 23 weeks, while greatly enhancing abdominal atheroma growth, produced no thoracic lesions. These results provide evidence that focal proliferation of intimal smooth muscle cells, a critical early event in atherogenesis, can be produced by an initiation-promotion treatment sequence.
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PMID:Focal smooth muscle proliferation in the aortic intima produced by an initiation-promotion sequence. 392 78

The hormonal system is a communication system between cells and organs. Hence it is not surprising that it influences almost all physiological functions and, at least partially, our behaviour and fate. The sexual phenotype is determined by the sex hormones. Normally, the phenotype is in accordance with gonadal and genetic sex, but occasionally, as a consequence of enzymatic defects in the biosynthesis of sex hormones or of androgen resistance, gonadal and genetic sex are in discordance with the phenotype, the latter determining generally the civil sex and the sex of rearing. Whereas the gender role is generally determined by the sex of rearing and the phenotype, itself under hormonal influence, homo- and transsexuality constitute notorious exceptions to this rule. Although several authors consider homo- and transsexuality to be the consequence of an impairment in androgenic impregnation in the perinatal period, there are at present no convincing arguments for an hormonal origin for either homo- or transsexuality, although such a possibility can't be excluded either. Besides their role in psychosexual behaviour, sex hormones play also a role in our life expectancy. Indeed, although maximal life expectancy of man is genetically determined, a major determinant of individual life expectancy is cardiovascular pathology. The latter is partly responsible for the difference in life expectancy between men and women, cardiovascular mortality increasing rapidly at menopause and being halved by oestrogen replacement therapy. Also atherogenesis as such is, to a large extend, under hormonal control. Indeed insulin resistance and hyperinsulinism, which develop as a corollary of the aging process, is an important cause of atherosclerosis as well as of hypertension. Other hormones also play an important role in our behaviour. We can mention here the role of the thyroid hormones in the physical and mental development of children as well as in the regression of the intellectual functions in hypothyroidism; the role of growth (and sex) hormones in the clinical symptomatology of aging; the memory enhancing effects of the antidiuretic hormone; the role of growth factors (as well as of sex hormones) in tumorigenesis; the role of corticoids (and sex hormones) in the modulation of immunological processes etc. In brief, hormones influence all aspects of our life.
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PMID:[Do hormones determine our fate?]. 820 84

Platelet-derived growth factor (PDGF) is a potent mitogen consisting of heterodimers of two distinct but homologous polypeptide chains, denoted A and B. PDGF-like homodimers of the A- and B-chains have been isolated, as well as two distinct receptor types (alpha and beta), which discriminate among the PDGF isoforms. The PDGF A- and B-chains are encoded by distinct genes located on human chromosomes 7 and 22, respectively. Although PDGF has been implicated as an important participant in development, tissue repair, and numerous pathologic states including tumorigenesis, atherosclerosis and inflammation, the mechanisms which determine the rate of its synthesis are only beginning to be understood. Basal expression of the PDGF A- and B-chain genes has been characterized in a number of cell types and is directed in part by elements in the respective proximal promoter-regulatory regions of the two genes. In addition, the first intron of PDGF-B has been shown to contain both positive and negative regulatory elements. Transcription of the PDGF subunit genes is inducible by a wide variety of mitogenic growth factors, cytokines and other agonists. These agents produce a rapid increase in steady-state concentrations of PDGF A- and B-chain mRNAs, peaking within 4-8 h of stimulation. The inductive effects of protein kinase C-activating phorbol 12-myristate 13-acetate (PMA), thrombin and transforming growth factor-beta (TGF-beta) are mediated through increases in the transcription rates of both genes. In addition, cAMP blocks the increases in transcription of the B-chain gene induced by thrombin and TGF-beta. Studies have demonstrated the importance of sequences immediately upstream of the B-chain transcription start site for induction in response to PMA-initiated megakaryocyte differentiation, an effect which is dependent on protein synthesis. However, cis-acting elements which mediate more rapid transcriptional induction seen in endothelial cells and astrocytes have yet to be identified in the proximal 5'-flanking sequences of either the A- or B-chain genes, suggesting that such events may be mediated by elements located outside of this region.
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PMID:Transcriptional control of the platelet-derived growth factor subunit genes. 834 77

Each cell is functionally restricted by differentiation, which determines its complement of active and inactive genes. Various diseases then become manifest in each cell, depending on these specific gene combinations. Neoplasia, for example, is due to a multistep series of genetic mutations. It is common in continuous replicators such as bronchial epithelium, colon, and marrow but rare in intermittent replicators such as endothelial and smooth muscle cells. In contrast, these latter cell types are centrally involved in degenerative phenomena such as atherosclerosis. However, in both continuous and intermittent replicators, reduction of gratuitous cell turnover will be of great benefit. The nonreplicating adult neuron almost never undergoes tumorigenesis compared with glial cells but gives rise to a variety of age-related degenerative diseases such as Alzheimer's or Parkinson's disease. In the nonreplicating neuron, therefore, it is imperative that we promote strategies to preserve cell viability by minimizing oxidative damage. Natural antioxidants such as vitamin C and E and beta carotene, as well as an optimal caloric and protein intake, should be cornerstones of treatment and prevention for the aging patient. A place for pharmacologic intervention is also likely soon. Current research should soon identify the precise mechanisms responsible for programmed cellular senescence and oxidative cellular damage so as to illuminate additional means of rational treatment, and perhaps more importantly, prevention.
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PMID:The biology of aging: looking to defuse the genetic time bomb. 836 65

Graft rejection is a baffling problem in organ transplantation which has so far no successful resolution. Present antirejection therapy is expensive, toxic, susceptible to infection, oncogenesis and atherosclerosis. With the use of 2 extremely histoincompatible strains of rats as model, it was found that when six donor splenocytes preconditioned by an extract from the culture medium of streptomyces caespitosus were injected into the host, after 2 weeks immune tolerance heterotopic transplanted donor hearts could survive normally more than 100 days without using any anti-rejection drug. Their mean survival time was 141.4 +/- 2.56 days, while that in the control group was only 11.7 +/- 3.48 days (P < 0.005). Thus, the present research offers some bright prospects in the area of organ transplantation.
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PMID:Long-term survival of heterotopic heart transplants in allogenic rats without using anti-rejection drugs after inducing immune tolerance. 872 37

Israel has one of the highest dietary polyunsaturated/saturated fat ratios in the world; the consumption of omega-6 polyunsaturated fatty acids (PUFA) is about 8% higher than in the USA, and 10-12% higher than in most European countries. In fact, Israeli Jews may be regarded as a population-based dietary experiment of the effect of a high omega-6 PUFA diet, a diet that until recently was widely recommended. Despite such national habits, there is paradoxically a high prevalence of cardiovascular diseases, hypertension, non-insulin-dependent diabetes mellitus and obesity-all diseases that are associated with hyperinsulinemia (HI) and insulin resistance (IR), and grouped together as the insulin resistance syndrome or syndrome X. There is also an increased cancer incidence and mortality rate, especially in women, compared with western countries. Studies suggest that high omega-6 linoleic acid consumption might aggravate HI and IR, in addition to being a substrate for lipid peroxidation and free radical formation. Thus, rather than being beneficial, high omega-6 PUFA diets may have some long-term side effects, within the cluster of hyperinsulinemia, atherosclerosis and tumorigenesis.
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PMID:Diet and disease--the Israeli paradox: possible dangers of a high omega-6 polyunsaturated fatty acid diet. 896 90

The transforming growth factor beta 1 (TGF beta 1) signalling pathway is important in embryogenesis and has been implicated in hereditary haemorrhagic telangiectasia (HHT), atherosclerosis, tumorigenesis and immunomodulation. Therefore, identification of factors which modulate TGF beta 1 bioactivity in vivo is important. On a mixed genetic background, approximately 50% Tgfb1-/- conceptuses die midgestation from defective yolk sac vasculogenesis. The other half are developmentally normal but die three weeks postpartum. Intriguingly, the vascular defects of Tgfb1-/- mice share histological similarities to lesions seen in HHT patients. It has been suggested that dichotomy in Tgfb1-/- lethal phenotypes is due to maternal TGF beta 1 rescue of some, but not all, Tgfb1-/- embryos12. Here we show that the Tgfb1-/- phenotype depends on the genetic background of the conceptus. In NIH/Ola, C57BL/6J/Ola and F1 conceptuses, Tgfb1-/- lethality can be categorized into three developmental classes. A major codominant modifier gene of embryo lethality was mapped to proximal mouse chromosome 5, using a genome scan for non-mendelian distribution of alleles in Tgfb1-/- neonatal animals which survive prenatal lethality. This gene accounts for around three quarters of the genetic effect between mouse strains and can, in part, explain the distribution of the three lethal phenotypes. This approach, using neonatal DNA samples, is generally applicable to identification of loci that influence the effect of early embryonic lethal mutations, thus furthering knowledge of genetic interactions that occur during early mammalian development in vivo.
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PMID:Mapping of a major genetic modifier of embryonic lethality in TGF beta 1 knockout mice. 902 Aug 52


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