Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An inflammatory cardiomyopathy may develop in humans and experimental animals with chronic Trypanosoma cruzi infection (Chagas' disease). Among the possible mechanisms involved in the pathogenesis of Chagas' cardiomyopathy, induction of heart-specific autoimmune responses has recently received substantial experimental support. The goal of the current study was to determine whether cardiac Ag-specific antibodies are produced in T. cruzi-infected mice with heart disease and, if so, to determine their Ag specificities. Upon infection with the Brazil strain of T. cruzi, C57BL/6 mice develop a cardiomyopathy that is histologically similar to that observed in chronically infected humans. Antisera from these mice were found to react with three cardiac Ag, having relative molecular masses of 200, 150, and 53 kDa. p200 and p150 are specifically found in heart muscle, although p53 is found in skeletal muscle as well. C57BL/6 mice infected with the Guayas strain of T. cruzi, which do not develop cardiomyopathy, did not produce antibodies to p200, p150, or p53, indicating that these antibodies may be specific markers of cardiomyopathy. Finally, p200 and p53 were identified as the contractile protein myosin and the intermediate filament protein desmin, respectively. This last finding is of special interest, because antibodies specific for myosin or desmin have been detected in humans and experimental animals with other natural and experimental cardiomyopathies. This suggests that infection with particular strains of T. cruzi may lead to the development of a cardiac Ag-specific autoimmune disease, possibly involving one or more of the Ag identified in this study.
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PMID:Cardiac antigen-specific autoantibody production is associated with cardiomyopathy in Trypanosoma cruzi-infected mice. 830 Nov 48

The micropathology of chronic Chagas' myocarditis reveals foci of myocardial cell loss associated with an inflammatory infiltrate composed predominantly of lymphomononuclear cells and interstitial fibrosis. The loss of myocardial cells, a devastating phenomenon in this cardiopathy, has been classically attributed to necrosis. In the present study we examined whether the loss of myocardial cells in human chronic Chagas' heart disease could result from cell death by apoptosis. A total of 11 cases of chronic chagasic myocarditis were studied: four hearts were obtained at autopsy within 8 h after death and seven endomyocardial biopsies were taken from chagasic patients with an arrhythmogenic form of the disease. The coronary arteries of all chagasic cases showed no obstructive lesions. The diagnosis of Chagas' disease was based on previously established criteria. Five cases were selected as controls: three hearts were obtained at autopsy within 8 h after death and two endomyocardial biopsies were taken from nonchagasic patients with normal myocardium morphology. As positive controls we used cardiac muscles of myocardial infarction and rat mammary glands on the fourth day after weaning. The TUNEL method was used to identify apoptotic cells in the myocardium. The expression of p53 protein, which directly or indirectly triggers apoptosis, was evaluated using immunohistochemical technique. A few apoptotic cells were stained in chronic chagasic hearts, both biopsy and autopsy cases. However, the stained nuclei were restricted to the mononuclear infiltrate accounting for about 0.5% of the mononuclear cells in the infiltrate. In contrast, the nuclei of cardiomyocytes in both regions bordering on and distant from the microfoci of myocardial cell loss were not stained by the TUNEL method. Moreover, the expression of the protein p53 in cardiomyocytes in chagasic hearts was absent. The results of the present study demonstrating negative in situ labeling of fragmented DNA associated with absence of expression of p53 provide support to the hypothesis that apoptosis is not the mechanism of cell death in chronic chagasic myocarditis. This reinforces the general opinion that the loss of cardiac muscle fibers in chagasic cardiopathy is produced by necrosis. On the other hand, the present results give support to the concept that apoptosis probably play a role in the clearing of lymphomononuclear cells in the inflammatory infiltrate in chronic chagasic myocarditis.
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PMID:Is apoptosis a mechanism of cell death of cardiomyocytes in chronic chagasic myocarditis? 1021 85

Adequate control of survival or programmed cell death (apoptosis) of cardiovascular cells appears as an important drug target. While prevention of apoptotic death of cardiomyocytes has been assessed in detail, selective induction of apoptosis of vascular smooth muscle cells or fibroblasts could also be of relevance. Thus, induction of apoptosis of vascular smooth muscle cells by p65 NF-kappa B and Bcl-xL antisense oligonucleotides or p53 overexpression could be useful for limiting vascular lesions associated with restenosis. Although fibroblasts represent the majority of cardiac cells, few attempts were made to induce fibroblast apoptosis in disorders associated with excessive collagen deposition and fibrosis. It is hypothesized that early interference with fibroblast proliferation after myocardial infarction or inflammatory heart disease limits fibrosis which further impairs cardiac performance. A candidate approach could involve growth factor analogues which are known to induce fibroblast apoptosis when an incomplete growth stimulus persists.
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PMID:Control of apoptosis of cardiovascular fibroblasts: a novel drug target. 1041 46

This investigation focused on whether apoptosis can be observed in some heart diseases. Apoptosis was examined immunochemically using monoclonal antibodies such as p53, Bcl-2 and cyclin E, A, and B1 in parallel with flow cytometry. Left ventricular myocardium was obtained at autopsy from 40 patients with acute myocarditis (AM; N = 10, 6 males, 4 females, mean age 56 +/- 13 years), chronic myocarditis (CM; N = 10, 5 males, 5 females, mean age 48 +/- 16 years), dilated cardiomyopathy (DCM; N = 10, 7 males, 3 females, mean age 60 +/- 11 years), and no heart disease (Cont; N = 10, 5 males, 5 females, mean age 63 +/- 14 years). Cell cycle analysis of myocytes by flow cytometry revealed that the relative content of G2M phase in acute myocarditis was far higher than those in other heart diseases (AM, 12.3 +/- 3.7%; CM, 5.2 +/- 4.5%; DCM, 6.3 +/- 4.0%; Cont, 3.4 +/- 1.8%; Mean +/- SD). Expression of p53 was observed mainly in myocytes from chronic myocarditis. Expression of Bcl-2, on the other hand, was detected in myocytes from acute myocarditis. Results suggest that apoptosis may play some role in the repairing process of myocardial inflammation.
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PMID:Stress signal to survival and apoptosis. 1041 52

Several epidemiological studies have found a weak, but consistent association between lung cancer in nonsmokers and exposure to environmental tobacco smoke (ETS). In addition, a purported link between such exposure and coronary heart disease (CHD) has been of major concern. Although it is biologically plausible that ETS has a contributory role in the induction of lung cancer in nonsmoking individuals, dose-response extrapolation-supported by the more solid database for active smokers-gives an additional risk for lung cancer risk that is more than one order of magnitude lower than that indicated by major positive epidemiological studies. The discrepancy between available epidemiological data and dosimetric estimates seems, to a major part, to reflect certain systematic biases in the former that are difficult to control by statistical analysis when dealing with risks of such low magnitudes. These include, most importantly, misclassification of smoking status, followed by inappropriate selection of controls, as well as certain confounding factors mainly related to lifestyle, and possibly also hereditary disposition. A significant part of an association between lung cancer and exposure to ETS would disappear, if, on the average, 1 patient out of 20 nonsmoking cases had failed to tell the interviewer that he had, in fact, recently stopped smoking. In the large International Agency for Research on Cancer (IARC) multicenter study even lower misclassification rates would abolish the weak, statistically nonsignificant associations that were found. In the former study an apparent significant protective effect from exposure to ETS in childhood with respect to lung cancer later in life was reported, a most surprising finding. The fact that the mutation spectrum of the p53 tumor suppressor gene in lung tumors of ETS-exposed nonsmokers generally differs from that found in tumors of active smokers lends additional support to the notion that the majority of tumors found in ETS-exposed nonsmokers have nothing to do with tobacco smoke. The one-sided preoccupation with ETS as a causative factor of lung cancer in nonsmokers may seriously hinder the elucidation of the multifactorial etiology of these tumors. Due to the high prevalence of cardiovascular disease in the population, even a modest causal association with ETS would, if valid, constitute a serious public health problem. By pooling data from 20 published studies on ETS and heart disease, some of which reported higher risks than is known to be caused by active smoking, a statistically significant association with spousal smoking is obtained. However, in most of these studies, many of the most common confounding risk factors were ignored and there appears to be insufficient evidence to support an association between exposure to ETS and CHD. Further, it seems highly improbable that exposure to a concentration of tobacco smoke at a level that is generally much less than 1% of that inhaled by a smoker could result in an excess risk for CHD that-as has been claimed-is some 30% to 50% of that found in active smokers. There are certainly valid reasons to limit exposure to ETS as well as to other air pollutants in places such as offices and homes in order to improve indoor air quality. This goal can be achieved, however, without the introduction of an extremist legislation based on a negligible risk of lung cancer as well as an unsupported and highly hypothetical risk for CHD.
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PMID:Environmental tobacco smoke revisited: the reliability of the data used for risk assessment. 1172 24

The effects of ethanol and ethanol-derived acetaldehyde on rat myocardial apoptosis and expression of genes involved in the regulation of apoptosis and cell cycle arrest were studied. Combined ethanol and calcium carbimide treatment for 2, 5 or 8 days (E + CC) markedly increased blood acetaldehyde levels. Cytosolic DNA fragmentation was quantified in the 5-day treatment group. Increased amount of DNA-fragmentation, reflecting increased apoptosis, was evident in the E + CC group (23% increase compared to controls). mRNA levels of genes regulating apoptosis were measured by using quantitative PCR in the 2- and 8-day treatment groups. In the 2-day treatment group, p21 gene expression was increased by 25% and bax/bcl-2 mRNA ratio by 57% in E + CC, compared to the control, group. In the 8-day treatment group, p21 mRNA level was 24% lower, p53 mRNA level was 15% higher (P < 0.005), and bcl-2 mRNA level 36% higher in E + CC-treated, compared to the control, group. Interestingly, both ethanol and calcium carbimide treatments alone increased bax mRNA levels, as compared to the control group at 2 and 8 days. These results indicate that acetaldehyde might regulate the expression of apoptosis-linked genes and that apoptosis of myocardial cells may be involved in the development of alcoholic heart disease.
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PMID:Combined calcium carbimide and ethanol treatment induces high blood acetaldehyde levels, myocardial apoptosis and altered expression of apoptosis-regulating genes in rat. 1200 8

Apoptosis, along with cellular proliferation, plays a major role in normal developmental processes and tissue homeostasis. We hypothesized that altered apoptosis-related pathways and/or reduced cell proliferation might play a role in the thymic hypoplasia or aplasia in DiGeorge syndrome (DG). We used immunohistochemistry to evaluate the apoptosis-related antigens Fas (CD95), bcl-2, and p53, as well as Mib-1 proliferation index in the thymuses from six patients with DG. The results were compared with those from the thymuses from six patients with non-DG congenital heart disease. All DG patients (age 32 weeks GA to 4 months) had hypoplastic thymuses ranging from microscopic foci to 2.7 g in weight (expected for age, 4.7 +/- 3.6 g to 10 +/- 6 g). The thymic weights from the patients with non-DG congenital heart disease (age 37 weeks GA to 1 month) ranged from 3 to 5.6 g and were at the lower range of expected weight by age (expected for age, 8.4 +/- 5.6 g to 12 +/- 7 g). All thymuses showed histologic features of stress-induced involution. In both groups, a - 50% Mib-1 proliferation index was found in the cortical thymocytes, whereas <5% Mib-1 labeling was seen in the medullary thymocytes; Fas stained medullary epithelial cells (3+) and cortical epithelial cells (1+); bcl-2 stained medullary thymocytes (3+) and cortical thymocytes (1+); p53 stained less than 1% of nuclei in all sections. No significantly altered Mib-1 proliferation index or expression of Fas, bcl-2, and p53 was observed in the hypoplastic thymuses in DG, compared to these same measures in non-DG. These results suggest that thymic hypoplasia in DG may be mediated by mechanisms other than reduced cellular proliferation and/or altered Fas, bcl-2, and p53 apoptotic pathways.
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PMID:Expression of apoptosis-related antigens, Fas, bcl-2, and p53, and Mib-1 proliferation index in the hypoplastic thymus of DiGeorge syndrome. 1220 98

Cigarette smoking as an addictive habit has accompanied human beings for more than 4 centuries. It is also one of the most potent and prevalent environmental health risks human beings are exposed to, and it is responsible for more than 1000 deaths each day in the United States. With recent research progress, it becomes clear that cigarette smoking can cause almost all major diseases prevalent today, such as cancer or heart disease. These detrimental effects are not only present in active smokers who choose the risk, but also to innocent bystanders, as passive smokers, who are exposed to cigarettes not-by-choice. While the cigarette-induced harm to human health is indiscriminate and severe, the degree of damage also varies from individual to individual. This intersubject variability in cigarette-induced pathologies is partly mediated by genetic variants of genes that may participate in detoxification process, eg, cytochrome P450 (CYP), cellular susceptibility to toxins, such as p53, or disease development. Through population studies, we have learned that certain CYP1A1 variants, such as Mspl polymorphism, may render the carriers more susceptible to cigarette-induced lung cancer or severe coronary atherosclerosis. The endothelial nitric oxide synthase intron 4 rare allele homozygotes are more likely to have myocardial infarction if they also smoke. In vitro experimental approach has further demonstrated that cigarettes may specifically regulate these genes in genotype-dependent fashion. While we still know little about genetic basis and molecular pathways for cigarette-induced pathological changes, understanding these mechanisms will be of great value in designing strategies to further reduce smoking in targeted populations, and to implement more effective measures in prevention and treatment of cigarette-induced diseases.
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PMID:Genetic influence on cigarette-induced cardiovascular disease. 1270 94

Flavonoids (FVs) are an important class of plant compounds postulated to be one of the constituents responsible for the beneficial effects of fruits and vegetables on health, including heart disease and cancer. At pharmacological levels, various naturally-occurring flavonoids have been shown to be cancer-protective in a variety of animal models and flavonoid derivatives, such as flavopyridol, are being assessed as chemotherapy drugs in clinical trials. This report has investigated the effects of the most common dietary FVs on several major signalling pathways in biopsies of human epithelial cells using primary cultures freshly isolated from biopsies and has obtained evidence for the previously unrecognised importance of stress kinase responses induced by kaempferol (KF), apigenin (AP) and luteolin (LU). KF, AP and LU all activated ATM/ATR (mutated in ataxia-telangiectasia and related) kinases and the p38 stress kinase and this was associated with induction of GADD45 and cell cycle arrest in G2, but not induction of apoptosis. These effects were not due to general toxicity since they were reversible on removal of FV. The inductions of ATM/ATR and p38 were functionally important since caffeine, an inhibitor of ATM/ATR, and the p38-specific inhibitor, SB203580, prevented induction of GADD45 and growth arrest by these three flavonoids. In contrast, although quercetin (QU) activated ATM (but not ATR), it did not activate p38 kinase, GADD45 or p53. QU may interfere with one of the lipoxygenase (LOX) pathways since the growth inhibitory effects of QU (but not the other three flavonoids) could be reversed by addition of LOX metabolites, particularly 12- and 15-hydroxyeicostetraenic acids.
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PMID:Effects of dietary flavonoids on major signal transduction pathways in human epithelial cells. 1460 32

Heart remodeling is associated with the loss of cardiomyocytes and increase of fibrous tissue owing to abnormal mechanical load in a number of heart disease conditions. In present study, a well-described in vitro sustained stretch model was employed to study mechanical stretch-induced responses in both neonatal cardiomyocytes and cardiac fibroblasts. Cardiomyocytes, but not cardiac fibroblasts, underwent mitochondria-dependent apoptosis as evidenced by cytochrome c (cyto c) and Smac/DIABLO release from mitochondria into cytosol accompanied by mitochondrial membrane potential (Deltapsi(m)) reduction, indicative of mitochondrial permeability transition pore (PTP) opening. Cyclosporin A, an inhibitor of PTP, inhibited stretch-induced cyto c release, Deltapsi(m) reduction and apoptosis, suggesting an important role of mitochondrial PTP in stretch-induced apoptosis. The stretch also resulted in increased expression of the pro-apoptotic Bcl-2 family proteins, including Bax and Bad, in cardiomyocytes, but not in fibroblasts. Bax was accumulated in mitochondria following stretch. Cell permeable Bid-BH3 peptide could induce and facilitate stretch-induced apoptosis and Deltapsi(m) reduction in cardiomyocytes. These results suggest that Bcl-2 family proteins play an important role in coupling stretch signaling to mitochondrial death machinery, probably by targeting to PTP. Interestingly, the levels of p53 were increased at 12 h after stretch although we observed that Bax upregulation and apoptosis occurred as early as 1 h. Adenovirus delivered dominant negative p53 blocked Bax upregulation in cardiomyocytes but showed partial effect on preventing stretch-induced apoptosis, suggesting that p53 was only partially involved in mediating stretch-induced apoptosis. Furthermore, we showed that p21 was upregulated and cyclin B1 was downregulated only in cardiac fibroblasts, which may be associated with G2/M accumulation in response to mechanical stretch.
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PMID:Mechanical stretch induces mitochondria-dependent apoptosis in neonatal rat cardiomyocytes and G2/M accumulation in cardiac fibroblasts. 1504 Aug 86


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