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Query: UNIPROT:P06889 (Mol)
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In order to address the question whether the virus or immune reactions to the heart induce cardiac damage in the murine model of coxsackievirus B3 induced myocarditis, calcium-resistant cardiac myocytes of a myocarditis susceptible strain of mice were isolated and exposed to myocarditic coxsackievirus B3. The tetrazolium salt MTT was used to visualize the effect of the virus upon cell viability by inverse light microscopy and by an EA test. Coxsackievirus B3 infected isolated adult cardiac myocytes as well as infected cultured cardiac fibroblasts were examined. In vitro the virus killed the myocytes within 16 h of infection whereas the fibroblasts survived the infection. Since coxsackievirus B3 is able to kill cardiac myocytes by itself, immunosuppressive treatment of acute coxsackievirus B3 induced myocarditis may be harmful by eliminating host immune defence mechanisms and, therefore, may lead to an enhanced viral spread and virus induced myocyte necrosis in the heart.
J Mol Cell Cardiol 1994 Jul
PMID:Coxsackievirus B3 infection leads to cell death of cardiac myocytes. 796 59

In susceptible DBA/2 mice coxsackievirus B 3-induced myocarditis leads to inflammatory and necrotic lesions in the myocardium 7-10 days after virus inoculation. The purpose of this study was to determine whether hemodynamic changes occur in murine coxsackievirus B 3 myocarditis and whether they are correlated to histological cardiac lesions throughout the infection. Left ventricular function was determined by open chest puncture of the left ventricle in the course of acute coxsackievirus B 3 infection. Histological cross sections of the heart were stained with hematoxylin/eosin and scored blindly for myocarditic lesions. Left ventricular function was preserved until day 7 post-virus inoculation Left ventricular systolic pressure, +dP/dtmax and -dP/dtmax and heart rate declined significantly from day 7 to day 10. The decrease in these parameters did not correlate with viral concentrations in the heart on the day of hemodynamic measurements. The decrease was related to histological changes on day 10, but not on day 7 of the infection. The data suggest (a) that a cumulative loss of cardiac myofibers, induced either by the virus and/or by immune reactions to the heart, is likely to lead to a late depression of cardiac function, and (b) that there is a weak and only temporary structure-function relationship in the heart in coxsackievirus B 3 myocarditis. Therefore, in addition to an analysis of histological changes, the measurement of cardiac function appears to be very important in order to completely evaluate the severity of myocarditis and the usefulness of any therapy.
J Mol Cell Cardiol 1995 Aug
PMID:Left ventricular hemodynamic parameters in the course of acute experimental coxsackievirus B 3 myocarditis. 852 20

Cultured human myocardial fibroblasts of pediatric origin seem to be a useful species-specific model for studying various heart diseases which involve the myocardial interstitium, for example enterovirus heart disease. Cells were propagated from small samples of human ventricular tissues (0.2 g) obtained from standard surgical procedure for the correction of Fallot-tetralogy. Cultured cells exhibited typical fibroblastoid morphology over a period of 4 months and were uniformly immunoreactive with a monoclonal antibody directed against prolyl-4-hydroxylase, a marker enzyme of fibroblasts. Infection of cell cultures with coxsackievirus B3, a cardiotropic enterovirus, resulted in a typical carrier-state type of virus persistence. Average virus titers of 2.3 x 10(5) plaque-forming units/ml (SD = 9.9 x 10(4)) were maintained over a period of up to 10 weeks by productive infection of about 8-10% of the cell population. Coxsackievirus B3 carrier cultures of human myocardial fibroblasts were used to evaluate in vitro the long-term antiviral effects of recombinant interferon alpha-2a and natural human interferon-alpha. Recombinant interferon-alpha reduced virus yields by 90% with a concentration of 423 IU/ml, whereas with natural interferon-alpha a 90% reduction of virus yields was achieved with concentrations as low as 21 IU/ml. Antiviral effects of both recombinant and natural interferon-alpha were highly specific and not related to inhibition of cell-proliferation (< 50% with interferon-alpha concentrations as high as 6250 IU/ml). Since effective concentrations of interferon-alpha can be easily attained in vivo with subcutaneous application, interferon-alpha (in particular: natural interferon-alpha) may become useful in the treatment of patients with enterovirus myocarditis and enterovirus induced dilated cardiomyopathy.
J Mol Cell Cardiol 1995 Oct
PMID:Cultured human myocardial fibroblasts of pediatric origin: natural human interferon-alpha is more effective than recombinant interferon-alpha 2a in carrier-state coxsackievirus B3 replication. 857 36

The Enterovirus may be the most common agent responsible for viral myocarditis and cardiomyopathy. Very little of the literature is available concerning the follow-up of patients who underwent transplantation with enteroviral positivity in native hearts. In the present study, 45 explanted hearts from patients who underwent orthotopic heart transplant at University of Padova were studied by reverse transcriptase (RT)-polymerase chain reaction (PCR): 27 patients had dilated cardiomyopathy (DC), 12 had ischemic cardiopathy (IC), 2 had valvular disease (VD), 2 had arrhythmogenic right ventricular cardiomyopathy (ARVC), 1 had giant cell myocarditis (GCM), and 1 had lymphocytic myocarditis (LM). Two sets of PCR primers from the highly conserved region of Enterovirus and Rhinovirus were used. Samples of both ventricles and septum were analyzed in every patients. The RT-PCR and nucleotide sequencing of amplicons were also performed on all post-transplantation follow-up biopsies in patients with Enterovirus positivity in the native heart. The viral genome was detectable in only 1 of 27 patients with DC (3%) and in 1 patient with LM. Nucleotide sequence analysis of the amplified product showed differences in nucleotide sequence of PCR samples compared with the sequence of the coxsackievirus B3 used in the current study. The patient with Enterovirus-positive DC showed a higher index of severe rejection (>3A) in the first 6 months, compared with the other patients tested. The patient with Enterovirus-positive LM died of disease recurrence 2 months after transplantation. The present study reveals a scarce presence of Enterovirus in the myocardium of patients with chronic myocardial disease. Because Enterovirus infection was predictive of a poor prognosis in these two patients, molecular studies are useful in excluding viral involvement in native hearts of transplanted patients.
Diagn Mol Pathol 1999 Mar
PMID:Enteroviral genome in native hearts may influence outcome of patients who undergo cardiac transplantation. 1040 92

Adenoviruses (Ad) are a significant cause of acute infections in humans; however, replication-defective forms of this virus are currently under investigation for human gene therapy. Approximately 20 to 25% of all the gene therapy trials (phases I to III) conducted over the past 10 years involve the use of Ad gene delivery for treatment inherited or acquired diseases. At present, the most promising applications involve the use of Ad vectors to irradicate certain nonmetastatic tumors and to promote angiogenesis in order to alleviate cardiovascular disease. While specific problems of using Ad vectors remain to be overcome (as is true for almost all viral and nonviral delivery methods), a distinct advantage of Ad is the extensive knowledge of its macromolecular structure, genome organization, sequence, and mode of replication. Moreover, significant information has also been acquired on the interaction of Ad particles with distinct host cell receptors, events which strongly affect virus tropism. This review provides an overview of the structure and function of Ad attachment (coxsackievirus and Ad receptor [CAR]) and internalization (alpha(v) integrins) receptors and discusses their precise role in virus infection and gene delivery. Recent structure studies of integrin-Ad complexes by cryoelectron microscopy are also highlighted. Finally, unanswered questions arising from the current state of knowledge of Ad-receptor interactions are presented in the context of improving Ad vectors for future human gene therapy applications.
Microbiol Mol Biol Rev 1999 Sep
PMID:Role of alpha(v) integrins in adenovirus cell entry and gene delivery. 1047 14

T cell vaccination regulates autoimmunity by the modification of helper and suppressor T cells. The present study was performed to examine whether T cell vaccination can prevent viral myocarditis in vivo. We used coxsackievirus B3 myocarditis in mice as an animal model with the analysis of lymphokine-activated killer cell activity. Vaccination of the mice with T lymphocytes significantly prolonged survival and improved cardiac histology of murine myocarditis. The effects of T cell vaccination were most evident when T cells sensitized with the same virus were used. Vaccination of the mice with T cells from other strains of mice showed lesser protective effects. Clearance of myocardial virus was not affected by this treatment. The efficacy of T cell vaccination was confirmed in vitro by the decrease of the lymphokine-activated killer cell activity against EL-4 tumor cells and cultured myocytes. T cell vaccination of mice prolonged survival and improved myocardial lesions of animals inoculated with coxsackievirus B3.
J Mol Cell Cardiol 2000 Dec
PMID:Protection against murine coxsackievirus B3 myocarditis by T cell vaccination. 1111 2

Full-length cDNA clones of RNA viruses are advantageous for maintaining the genomic sequence without the generation of diversity by accumulation of sequence mutations during productive virus replication. They permit in vitro manipulation of the genomic clone to test the effect of sequence changes on the phenotype of reactivated virus. Infectious cDNA clones have been produced by ligation of subgenomic clones but are sometimes difficult to generate in a single cloning operation. We used reverse-transcription to synthesize full-length cDNA from genomic RNA of Coxsackievirus B3 of the Picornavirus family and enzymatically amplified this by long PCR. Five different cloning vectors were used to clone the long PCR product, including the vector Lorist6 which contains transcriptional terminators on either side of the cloning site to prevent transcription of inserts in E. coli. No recombinant colonies were obtained from any of the vectors lacking transcriptional terminators but three full-length clones were obtained using Lorist6. The results suggest that transcriptional terminators increase the recovery of cDNA clones of the 7.4 kb Coxsackie virus genome in this cosmid vector, without resort to phage packaging, representing an advance over previous methods and advantages in the molecular manipulation of these viruses.
J Mol Microbiol Biotechnol 2002 Mar
PMID:A vector with transcriptional terminators increases efficiency of cloning of an RNA virus by reverse transcription long polymerase chain reaction. 1187 8

The left ventricle (LV) plays a central role in the maintenance of health of children and adults due to its role as the major pump of the heart. In cases of LV dysfunction, a significant percentage of affected individuals develop signs and symptoms of congestive heart failure (CHF), leading to the need for therapeutic intervention. Therapy for these patients include anticongestive medications and, in some, placement of devices such as aortic balloon pump or left ventricular assist device (LVAD), or cardiac transplantation. In the majority of patients the etiology is unknown, leading to the term idiopathic dilated cardiomyopathy (IDC). During the past decade, the basis of LV dysfunction has begun to unravel. In approximately 30-40% of cases, the disorder is inherited; autosomal dominant inheritance is most common (although X-linked, autosomal recessive and mitochondrial inheritance occurs). In the remaining patients, the disorder is presumed to be acquired, with inflammatory heart disease playing an important role. In the case of familial dilated cardiomyopathy (FDCM), the genetic basis is beginning to unfold. To date, two genes for X-linked FDCM (dystrophin, G4.5) have been identified and four genes for the autosomal dominant form (actin, desmin, lamin A/C, delta-sarcoglycan) have been described. In one form of inflammatory heart disease, coxsackievirus myocarditis, inflammatory mediators and dystrophin cleavage play a role in the development of LV dysfunction. In this review, we will describe the molecular genetics of LV dysfunction and provide evidence for a "final common pathway" responsible for the phenotype.
Curr Mol Med 2001 Mar
PMID:Molecular genetics of left ventricular dysfunction. 1189 44

Systemic administration of adenoviral vectors leads to a widespread distribution of vector. Therefore, targeting of adenoviral vectors to specific tissues or cell types will require methods to ablate the normal tropism of the vector simultaneously with the introduction of new receptor specificities. To inhibit native receptor binding, we mutated residues in the AB loop of the adenovirus type 5 (Ad5) fiber. We genetically incorporated the S408E-P409A mutation, referred to as KO1, into the adenoviral genome alone or in combination with an RGD-targeting ligand in the HI loop of fiber. Transduction experiments confirmed that the KO1 mutation results in a significant reduction in fiber-dependent gene transfer on A549 and primary fibroblast cells that could be restored via the RGD-targeting ligand. Competition transduction experiments verified the receptor-binding properties of each vector on A549 and hepatocytes in vitro. Unexpectedly, in mice systemic delivery of the vector containing the KO1 mutation resulted in efficient liver transduction that was localized specifically to hepatocytes. We confirmed these results in three different mouse strains, indicating that hepatic adenoviral gene transfer may be independent of the coxsackievirus-adenovirus receptor and that in vivo retargeting will require further viral capsid modifications to generate a fully detargeted adenoviral vector upon which to introduce new tropisms.
Mol Ther 2002 Jun
PMID:In vivo hepatic adenoviral gene delivery occurs independently of the coxsackievirus-adenovirus receptor. 1202 62

The aim of the present study was to explore the contribution of antibody-mediated immune enhancement in coxsackievirus B3(CB3) infection. Murine macrophage-like P388D1 cells were exposed to various concentrations of anti-CB3 immunoglobulin G (anti-CB3 IgG) or the Fab fragment of anti-CB3 IgG, and were infected with CB3 in Experiment I. High concentrations of anti-CB3 IgG showed a virus-neutralizing activity; however, a subneutralizing antibody concentration of IgG significantly enhanced virus replication. This infectious enhancement was blocked not only by the pretreatment of heat-aggregated gamma-globulin but by a specific Fc receptor (Fc gamma III/II receptor) antibody treatment. In contrast, the Fab fragment of anti-CB3 IgG did not enhance CB3 infection, but showed a rational neutralizing activity to CB3. These findings suggest the presence of Fc receptor mediated enhancement of CB3 infection in vitro. In Experiment II, C(3)H/He mice were inoculated with various amounts of an amyocarditic variant of CB3 followed 15 days later by myocarditic CB3. By this rechallenge, myocarditis was not induced in the mice with high neutralizing antibody titers. There was an inverse relationship between preexisting neutralizing antibody titers and the severity of myocarditis. The severity of myocarditis and myocardial CB3 titers, however, were markedly enhanced in the mice with a subneutralizing level of immunity compared to those with no immunity. The distribution of myocardial Fc receptor-bearing cells and serum macrophage inflammatory protein-2 levels paralleled the severity of myocarditis. By another virus rechallenge in Experiment III, enhanced infection of CB3 was not observed in vivo. These findings suggest that antibody-mediated immune enhancement might be involved in the pathogenesis of CB3 myocarditis.
J Mol Cell Cardiol 2002 Sep
PMID:Antibody-mediated immune enhancement in coxsackievirus B3 myocarditis. 1239 96


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