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Query: UNIPROT:P06889 (Mol)
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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

Recent studies of heart disease suggest that immunologically mediated processes often accompany cardiac injury and can contribute to pathogenesis. Murine models of myocarditis have provided insight into the mechanisms by which autoimmune responses to cardiac antigens arise and cause tissue pathology. It is now evident that T cells, cytokines and antibodies can all contribute to cardiac injury. Furthermore, murine models have demonstrated that both the propensity to develop autoreactivity following cardiac injury and the vulnerability of the heart to these responses are under genetic control. Continued studies will help to identify susceptibility genes and might aid in the development of strategies to protect individuals at risk from immunologically mediated damage following cardiac injury.
Mol Med Today 1996 Aug
PMID:Autoimmunity in heart disease: mechanisms and genetic susceptibility. 879 19

In patients with septic shock or inflammatory cardiac diseases like myocarditis myocardial contractility is depressed. These patients have elevated circulating levels of bacterial endotoxins (lipopolysaccharides, LPS) and pro-inflammatory cytokines like interleukin-1 beta (IL-alpha 1 beta) or tumor necrosis factor-alpha (TNF-alpha). It is not clear, whether LPS and/or cytokines have direct inotropic effects on cardiomyocytes and whether these effects are mediated via the L-arginine-nitric oxide synthase (NOS) pathway as demonstrated in vascular smooth muscle cells. Therefore, we examined the direct effects of LPS. IL-1 beta and TNF-alpha on contractility and cGMP content in isolated guinea-pig ventricular cardiomyocytes. Furthermore, the influence of the NOS inhibitor NG-nitro-L-arginine (L-NNA) and dexamethasone on these effects was studied as well as inducible NOS (iNOS) protein expression. LPS (1000 ng/ml), IL-1 beta (25 ng/ml) and TNF-alpha (100 ng/ml) decreased contractility by 48%, 55% and 65% and augmented cGMP content by 135%, 88% or 70% after long-term treatment (18 h) in cardiomyocytes, without altering contractility or cGMP content after short-term treatment (30 min). These effects were blocked by L-NNA (100 microM) and dexamethasone (3 microM). Furthermore iNOS protein was expressed in LPS- and cytokine-treated cardiomyocytes. These findings demonstrate that LPS. IL-1 beta and TNF-alpha have direct negative inotropic effects on cardiomyocytes, which are accompanied by an increase in cGMP content. These effects are mediated via de novo synthesis of a myocardial iNOS. The direct negative inotropic effects of endotoxins and cytokines on cardiomyocytes may in part contribute to the contractile dysfunction observed in patients with septic shock or inflammatory cardiac diseases.
J Mol Cell Cardiol 1996 Aug
PMID:Endotoxin and cytokines induce direct cardiodepressive effects in mammalian cardiomyocytes via induction of nitric oxide synthase. 887 73

We found recently autoantibodies against the adenine nucleotide translocator (ANT), a carrier in the inner mitochondrial membrane, in sera of patients with myocarditis and dilated cardiomyopathy. To elucidate whether these antibodies are of pathophysiological importance, we investigated the function and expression of the adenine nucleotide translocator (ANT) in the heart muscle tissue of patients suffering from myocarditis and DCM. We found a markedly lowered transport capacity of the translocator accompanied by an elevation in total ANT protein content. The alteration in ANT protein amount is caused by an ANT isoform shift characterized by an increase in ANT 1 isoform protein associated with a decrease in ANT 2 isoform and an unchanged ANT 3 content. It could be shown that the isoform shift is not a progressive process during the disease period but an event in the early period of illness which becomes permanent. Simulating the effect of pathogenetic factors of autoimmunological diseases, we infected A/J mice with the enterovirus Coxsackie B3 and immunized guinea pigs with myocardial ANT protein. Both treatments led to autoimmunological responds and to a lowered myocardial transport capacity of ANT, to a disturbed energy metabolism and consequently to a depression of heart function.
Mol Cell Biochem
PMID:Significance of the adenine nucleotide translocator in the pathogenesis of viral heart disease. 897 71

In myocarditis an antigen-specific immune response to cardiac epitopes has been demonstrated by several investigators. In 54 patients with histologically proven myocarditis, autoantibodies to cardiac tissue were observed in 73% of patients utilizing the indirect immunofluorescence test with human myocardium and adult heterologous cardiocytes. By immunoblot, 44% of sera from patients reacted with cardiac tissue. These antibodies were directed preferentially against proteins with the molecular weight of 43 up to 67 kDa. Three particular proteins were identified by the use of two-dimensional immunoblot and further characterized by amino acid sequence analysis. To characterize the epitopes recognized by the autoantibodies isoelectric focusing followed by SDS-PAGE was used to separate the complex mixture of proteins from human heart. Immunoblot analysis of antigens revealed proteins ranging from a size of 30-67 kDa at isoelectric points of 6.5-8.5 to be of particular interest. Five of these proteins have now been analyzed by N-terminal amino acid sequencing (Edman degradation). One was found to be creatine kinase and one was identified as a yet unknown protein. Three proteins were N-terminally blocked and were investigated further by enzymatical digestion, followed by separation of the usually complex peptide mixtures on HPLC. One of the peptides was found to be dihydrolipoamide dehydrogenase, a membrane enzyme, and one was identified as a sarcomere specific creatine kinase. Because these proteins are intracullularly located enzymes, their pathogenetic role as antigens for the autoantibodies remains to be elucidated further.
J Mol Cell Cardiol 1997 Jan
PMID:Autoantibodies in sera of patients with myocarditis: characterization of the corresponding proteins by isoelectric focusing and N-terminal sequence analysis. 904 23

The cardiac characteristics of the WBN/Kob rat resemble those of rats with catecholamine-induced myocarditis. To determine the etiology of these WBN cardiac characteristics, we assessed the number and affinity of beta-adrenergic receptors, and investigated adenylate cyclase activity, the cardiac myocyte cyclic adenosine monophosphate (cAMP) concentration and the activity of guanosine triphosphate (GTP)-binding protein in 3-month-old WBN/Kob rats. Age-matched Wistar rats served as controls. The mean number of beta-adrenergic receptors was similar in WBN/Kob and Wistar rats (28.0+/-9.1 v 28.3+/-8.9 fmol/mg protein), and there was no significant difference in beta-adrenergic receptor affinity between groups (1.09+/-0.54 v 1.26+/-0.60 nM). The mean cAMP concentration in cardiac myocytes was significantly higher in WBN/Kob rats than in Wistar rats 1975.6+/-247.8 v 344.9+/-83.6 pmol/g wet tissue), (P=0.0112) as was adenylate cyclase activity (33.61+/-8.32 v 24.3+/-12.78 pmol/mg/min), (P=0.0174). The activity of GTP-binding protein was significantly higher in WBN/Kob rats than in Wistar rats. After a beta-agonist binds to a beta-adrenergic receptor, activated adenylate cyclase produces cAMP in myocytes, which in turn opens the Ca2+ channel, leading to an influx of Ca2+ into myocytes. Our results suggest that the increase in adenylate cyclase activity in WBN/Kob rats have led to an increase in the cAMP concentration in myocytes. This process may have resulted in excessive beta-adrenergic activity due to high activity of GTP binding protein in WBN/Kob rats, which may explain the hypersensitivity of WBN/Kob rats to isoproterenol and the development of catecholamine-induced myocarditis.
J Mol Cell Cardiol 1997 Jan
PMID:Mechanism of cardiac involvement in the WBN/Kob rat. 904 39

Management of acute viral myocarditis is still controversial. Amrinone, a noncatecholamine nonglycoside bipyridine agent, produces sustained improvement of cardiac function and symptomatology in congestive heart failure (CHF). Amrinone demonstrates phosphodiesterase inhibitory activity that is relatively selective for the major phosphodiesterase isozyme in cardiac muscles, PDE III, which specifically hydrolyzes cyclic 3'5' adenosine monophosphate (cAMP). We investigated the effects of amrinone in an animal model of acute CHF related to myocarditis caused by the encephalomyocarditis virus (EMCV). Female C3H mice were inoculated intraperitoneally (i.p.) with 500 plaque-forming units of EMCV in 0.1 ml of saline. A total of 96 mice were randomly assigned to four groups. Each animal was administered 0.2 ml of phosphate-buffered saline (PBS) containing amrinone at a concentration of 1, 10, or 50 mg/kg, or PBS as an infected control, injected i.p. once daily for 21 days, starting on day 1 after viral inoculation. Each group contains 20 to 30 mice. Infected untreated mice survived at 80% (n = 16), however, only 13% (n = 16) of mice treated with amrinone (50 mg/kg) survived (p < 0.01). Downregulation of cardiac cAMP occurred 1 day after the viral infection. Although amrinone (10 and 50 mg/kg) treatment significantly (p < 0.05) increased the cardiac cAMP content and the dose of 10 mg/kg could potentially retard death from CHF due to viral myocarditis. The higher (50 mg/kg) doses of amrinone may produce unfavorable effects when used to treat mammals with viral myocarditis and CHF.
Res Commun Mol Pathol Pharmacol 1997 Jan
PMID:Effect of amrinone on murine viral myocarditis. 905 49

Application of molecular genetic tools to inherited cardiovascular disorders has provided important insights into the molecular mechanisms underlying cardiomyopathies, arrhythmias, blood pressure regulation, and atherosclerosis. In addition, alteration of gene expression has been observed under common cardiovascular conditions such as cardiac hypertrophy and heart failure. Recent advances in transgenic and gene-targeting approaches allow a sophisticated manipulation of the mouse genome by gene addition, gene deletion, or gene modifications. These transgenic models enable the dissection of in vivo pathways responsible for these complex disease phenotypes. This review describes tissue-specific promoters suitable for targeting candidate genes to the cardiovascular system as well as a number of valuable transgenic animal models of blood pressure regulation, atherogenesis, defects in the coagulation system, cardiac hypertrophy, myocarditis, cardiomyopathies, and heart failure. Limitations and difficulties associated with these transgenic approaches are discussed. Animal models which may provide a basis for future gene therapy of cardiovascular diseases are introduced. Finally, methods are described to regulate the spatial and temporal expression level of a transgene, to inactivate a target gene in a tissue-specific manner, and to introduce specific mutations into the genome. These recent advances in transgenic technology are expected to have a considerable impact on cardiovascular research in the near future.
J Mol Med (Berl) 1997 Feb
PMID:Transgenic animal models: new avenues in cardiovascular physiology. 908 29

Ribonuclease protection assay was used to demonstrate mRNA expression of several cytokines as well as inducible NO synthase (iNOS), constitutive endothelial NO synthase (cNOS) and perforin in the myocardium during the course of experimental autoimmune myocarditis (EAM) in rats. Interleukin 2 (IL-2) appeared in the initial inflammatory phase (day 14), subsided in the maximum inflammatory phase (day 19) and disappeared by the recovery phase (day 25). mRNA of IL-3 beta, interferon gamma INF-gamma and tumor necrosis factor alpha (TNF-alpha) were detected only in the maximum inflammatory phase and iNOS also appeared for several days at this time. In contrast. IL-10 mRNA was detected after the maximum inflammatory stage and persisted into the recovery phase (days 25-36). Although transforming growth factor beta 1 (TGF-beta 1) could be detected in all phases, the expression was markedly enhanced in the maximum inflammatory phase and gradually diminished (around day 36) to basal levels. Perforin mRNA was not detected at any point in the disease. Besides macrophages and CD4 T cells, a number of neutrophils were found in the myocardium especially at peak inflammatory stage. We suggest that antigen (Ag) primed Ag presenting cells or macrophages interact with T cells (Th1) to produce IL-2 and subsequent IFN-gamma, which further activates macrophages in the myocardium. Consequently, TNF-alpha and iNOS may inflict tissue damage to myocardium. It is also suggested that TGF-beta) and one representative Th2 cytokine, IL-10, help inhibit inflammation. These findings suggest that Th1 and Th2 cytokines are produced at different stages of EAM and modulate the inflammation and the course of EAM.
J Mol Cell Cardiol 1997 Feb
PMID:Characterization of cytokine and iNOS mRNA expression in situ during the course of experimental autoimmune myocarditis in rats. 914 Aug 9

The co-ordinate action of several cytokines determines the nature, severity and duration of myocarditis. Interleukin (IL)-12 mediates a broad range of effects on both innate and acquired immunity. However, the in vivo role of IL-12 in viral myocarditis remains to be elucidated. To clarify the role of IL-12 in viral myocarditis, we treated mice inoculated with the encephalomyocarditis virus (EMCV), with recombinant IL-12 and neutralizing anti-IL-12 antibody. The successive administration of 10 ng of IL-12 from the day of virus inoculation to 5 days thereafter, reduced mortality, myocardial damage and viral replication in the heart tissue. The gene expression of IL-12p35 and IL-12p40 was enhanced in the hearts of EMCV inoculated mice. Treatment with neutralizing anti-IL-12 resulted in increased mortality of mice inoculated with EMCV. In conclusion, endogenous and exogenous IL-12 play protective roles in murine viral myocarditis.
J Mol Cell Cardiol 1997 Sep
PMID:Protective role of interleukin-12 in viral myocarditis. 929 56


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