Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A trinucleotide repeat polymorphism in the MEF2A gene is described. MEF2A is expressed early in cardiac muscle development; thus the possibility of linkage between this polymorphism and familial cardiomyopathies was investigated in three families not linked to genes coding for known sarcomeric proteins. MEF2A was excluded as a candidate for dilated cardiomyopathy (DCM)(LOD of -9.03) and hypertrophic cardiomyopathy (HCM)(LODs of -5.43 and -2.44) in these families. Because expansion of triplet repeats has been shown to be responsible for several inherited diseases, 121 unrelated HCM probands and 28 unrelated DCM probands were examined for evidence of expansion of this repeat. No expansion of this trinucleotide repeat was seen in any of the 149 cardiomyopathy probands.
Mol Cell Probes 1997 Feb
PMID:Polymorphic trinucleotide repeat in the MEF2A gene at 15q26 is not expanded in familial cardiomyopathies. 907 15

An immunocytochemical study was performed to examine the expression of cellular c-myc protein in the heart of 30-, 120- and 180-day-old cardiomyopathic Syrian UM-X7.1 hamsters. The heart of age- and sex-matched BIO-RB hamster was used as normal control. In paraffin sections, an immunostaining for c-myc was markedly increased in cytoplasm of cells from the UM-X7.1 heart as compared with that of the BIO-RB heart which showed a weak staining. However, c-myc was localized in nuclei of cells in frozen sections of the heart. Specific cell types of the heart were differentiated with anti-vimentin, and we found that the increased expression of c-myc was present in nuclei of muscle cells of the UM-X7.1 myocardium. A quantitative study of c-myc-positive nuclei of muscle and nonmuscle cells was carried out by a video micrometer. The mean number of c-myc-positive nuclei of muscle cells was significantly higher in the cardiomyopathic heart than in the control heart from hamsters of all ages studied. These results suggest that the increase of c-myc protein may relate to the pathological state or pathogenesis of the hereditary cardiomyopathy.
Mol Cell Biochem 1997 Apr
PMID:Immunocytochemical detection of enhanced expression of c-myc protein in the heart of cardiomyopathic hamster. 908 33

The BIO14.6 hamster is a widely used model for autosomal recessive cardiomyopathy. These animals die prematurely from progressive myocardial necrosis and heart failure. The primary genetic defect leading to the cardiomyopathy is still unknown. Recently, a genetic linkage map localized the cardiomyopathy locus on hamster chromosome 9qa2.1-b1, excluding several candidate genes. We now demonstrate that the cardiomyopathy results from a mutation in the delta-sarcoglycan gene that maps to the disease locus. This mutation was completely coincident with the disease in backcross and F2 pedigrees. This constitutes the first animal model identified for human sarcoglycan disorders.
Hum Mol Genet 1997 Apr
PMID:Identification of the Syrian hamster cardiomyopathy gene. 909 66

An experimental model of early-stage cardiomyopathy was created by immunizing rabbits for 1 year with synthetic peptides corresponding to the sequence of the second extracellular loop of either beta-adrenoceptors or M2-muscarinic receptors. Thirty male rabbits were used and divided into three groups: a control group (n = 10), a group immunized with the peptide corresponding to the beta-adrenoceptor (beta 1 group) (n = 10) and a group immunized with the peptide corresponding to the M2-muscarinic receptor (M2 group) (n = 10). If the sera from both groups of immunized rabbits high-titres of anti-peptide antibodies were found throughout the study period but not in the sera from control rabbits or in the preimmune sera of immunized rabbits. No significant cross-reaction with peptides other than those used for immunization was found. The myocardial receptor density of both immunized groups displayed a strong trend toward receptor up-regulation. This was significant in the beta 1 group but not in the M2 group. Both groups of immunized rabbits displayed significantly enlarged ventricles and thinner walls, as compared with the control group. However, in contrast to the beta 1 group, which showed enlarged cavities in both left and right ventricles, the M2 group was mainly affected in the right ventricles. Moreover, morphological examinations of the hearts of rabbits from both immunized groups demonstrated focal myofibrillar lysis, loss of myofilament, mitochondrial swelling and condensation, sarcoplasmic vacuolation, deposition of dense granules in the sarcoplasm and the myofibrils. One of the sex control rabbit hearts which were examined showed mild degenerative changes in the myocardium and scant mononuclear cell infiltration. However, when all the control rabbit hearts were examined by electron microscopy, no significant alterations were found. These results suggest that immunization by peptides, corresponding to the target sequences for anti-receptor autoantibodies in idiopathic dilated cardiomyopathy, induces morphological changes in the heart similar to those found in the human disease.
J Mol Cell Cardiol 1997 Feb
PMID:Peptides derived from cardiovascular G-protein-coupled receptors induce morphological cardiomyopathic changes in immunized rabbits. 914 Aug 22

Myoglobin levels are decreased in various animal models of heart failure, a change that has been associated with compromised energy supply. The underlying mechanisms by which myoglobin content decreases in failing myocardium are unknown. Bovine hereditary cardiomyopathy (bCMP) displays several characteristics of human dilated cardiomyopathy with a marked desensitization of the beta-adrenoceptor signal cascade. The aim of the present study was to investigate whether a similar reduction of myoglobin can be seen in this animal model, and to elucidate the possible mechanism of this reduction. Myoglobin protein concentration was decreased by 46-47% (P < 0.05) in left and right ventricular myocardium of failing hearts (n = 9) compared to control hearts (n = 11). No difference was found between atria of diseased and control animals. Immunohistochemistry with a polyclonal antibody against myoglobin revealed a strong and uniform labeling in cardiomyocytes of non-failing hearts. Using microscopic densitometry, immunosignals were significantly decreased in ventricular myocytes of bCMP hearts (168 +/- 5.3 v 118 +/- 8.6 arbitrary units, P < 0.05). Moreover, myoglobin was heterogeneously distributed in bCMP hearts, with single myocytes showing no staining. Slot blot analysis of total RNA demonstrated a 40-50% reduction (P < 0.05) of myoglobin mRNA levels in ventricular but not in atrial myocardium of bCMP hearts. The results support the view that a decrease of myocardial myoglobin is a general phenomenon in end-stage heart failure. It appears to be primarily due to reduced gene expression but may be aggravated by leaking from single myocytes. The decrease of myoglobin may contribute to the imbalance between energy production and energy expenditure in heart failure.
J Mol Cell Cardiol 1997 Feb
PMID:Reduction of myocardial myoglobin in bovine dilated cardiomyopathy. 914 Aug 31

Although increased deposition of collagen proteins has been described in cardiomyopathy, little is known of the temporal relationship between events in collagen gene transcription and the occurrence of cardiac fibrosis, the removal of collagen by matrix metalloproteinases (MMPs), or of the regulation of these events by angiotensin AT1 receptors in this disease. We sought to study steady-state collagen mRNA abundance and the deposition of specific collagen subtypes in right and left ventricular muscle of Syrian cardiomyopathic (CMP) hamsters at different stages of cardiomyopathy. Using zymography, we also investigated the gelatinolytic activities of different MMPs to gain some information about collagen removal in experimental hearts. Finally, we investigated the effect of AT1 receptor blockade (losartan) on collagen remodeling. We observed that the mRNA levels of types I and III collagens were significantly increased in all four experimental groups (35, 65, 120, and 200 day) in left ventricular tissue when compared to control (F1-beta strain) values. The mRNA levels of these collagen species in experimental right ventricular tissue samples were only elevated significantly in the 35 and 200 day experimental groups when compared to controls. Fibrillar collagen deposition was elevated in left and right ventricular CMP samples after a lag period from the occurrence of corresponding increases in mRNA abundance. Although 2-week losartan treatment of 65, 120 and 200 day experimental groups had no significant effect on left ventricular fibrillar collagen concentration or collagen mRNA abundance when compared to vehicle-infused CMP hamsters, AT1 receptor blockade was associated with complete regression of cardiac hypertrophy. Both MMP-1 (54 kDa band) and MMP-2 (58 and 62 kDa bands) activities were increased in left ventricular CMP tissues at 65, 120 and 200 days when compared to F1-beta controls. Losartan treatment was associated with significant attenuation of MMP activities in cardiomyopathic samples at 65 and 120 days. Thus, elevation of mRNA abundance of fibrillar collagen genes occurs at very early stages in this model of cardiomyopathy, and corresponding collagen proteins were subsequently deposited in the cardiac interstitium at later stages. As collagen concentration was significantly increased in later stages of cardiomyopathy studied herein (120 and 200 day groups), our data support the hypothesis that collagen synthesis exceeds the capacity of collagen removal during the progression of cardiomyopathy. Nevertheless, cardiac collagen remodeling may be facilitated by elevated MMP activity in cardiomyopathic stages in this experimental model, and we suggested that attenuation of MMP activity in the presence of losartan may be a cardioprotective mechanism of this agent.
J Mol Cell Cardiol 1997 Jul
PMID:Cardiac collagen remodeling in the cardiomyopathic Syrian hamster and the effect of losartan. 923 38

A null mutation in the desmin gene has been introduced into the germ line of mice. Such mice develop and reproduce normally proving that desmin is not needed either for the formation of the heart or the alignment of functioning myofibrils. However, cardiovascular lesions and a skeletal myopathy were observed in growing and adult mice. In the present study we have carried out a detailed analysis of these cardiac lesions. Homozygous mutant mice, which were confirmed to lack expression of desmin mRNA and desmin protein in the heart, were revealed by electron microscopy to contain degenerating cardiomyocytes as early as 5 days post-partum. At 10 days post-partum and onwards the degeneration of cardiomyocytes gave rise to areas with an accumulation of macrophages, fibrosis and calcification preferentially in the inter-ventricular septum and the free wall of the right ventricle. The localization of the lesions mainly to these sites suggested that it is not the work load and contractions per se which were the pathogenic events leading to the cardiomyopathy. It might be that stress related to lengthening of the myocytes occur more in the right ventricle than in the left. At the ultrastructural level changes in the intercalated discs, disruption of the sarcolemma and supercontraction of myofibrils seemed to be the key events leading to cardiomyocyte death. Thus, the intermediate filaments are required to maintain the basic integrity of cardiomyocytes and especially the link between the intermediate filaments and the sarcolemma appear more important than previously realized.
J Mol Cell Cardiol 1997 Aug
PMID:Null mutation in the desmin gene gives rise to a cardiomyopathy. 928 43

The mechanisms for the progression of the anthracycline-induced cardiomyopathy to contractile failure has not been defined. In vitro, doxorubicin (DOX) appears to modify calcium-mediated excitation-contraction coupling, which depresses cardiac contractility. This study characterizes the onset of contractile failure associated with the development of DOX-induced cardiomyopathy. Rabbits were treated with DOX (1 mg/kg i.v. twice weekly, 12-18 doses; DOX-treated group) and compared with a pair-fed Control group infuse with saline vehicle. The severity of the cardiomyopathy was determined by numerically-scored histopathology. Myocardial contractility was determined in thin fiber bundles from right ventricular (RV) papillary muscles and left atria that were removed and mounted on a force transducer in oxygenated Krebs-bicarbonate buffer (pH=7.4 at 30 degrees C) to record the amplitude (DT) and maximum rate (+dT/dt ) of isometric tension. Myofibrillar and calcium loading properties were determined by the calcium and caffeine-activated tension responses respectively in chemically-permeabilized fibers. With the onset of the cardiomyopathy (score <2) DT at low frequency (0.5 Hz) was depressed (0.61+/-0.01 mN/mg; n=14) compared to Control (0.93+/-0.09 mN/mg; n=15). Contractility at higher rates (1 Hz) was not different in this DOX-treated and Control groups. Maximum calcium and caffeine-activated force and the pCa to half-maximum force of permeabilized fibers were comparable in DOX-treated and Control groups. The loss of contractility of the DOX-treated group was related to reduction in sarcoplasmic reticulum calcium release channel density, as determined by Bmax for 3H-ryanodine binding in cardiac microsomal membrane fraction. Post-rest potentiation of contractility, as well as frequency-dependent (0.25-1.5 Hz) and post-extrasystolic potentiation of contractility were preserved in the DOX-treated group. In vitro, DOX depressed post-rest potentiation of contractility. Thus, the onset of contractile failure of the DOX-induced cardiomyopathy is characterized by effects consistent with disordered calcium-mediated excitation-contraction coupling and these effects are qualitatively different than in vitro effects of DOX.
J Mol Cell Cardiol 1997 Oct
PMID:Contractile failure in chronic doxorubicin-induced cardiomyopathy. 934 58

Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked inherited disease characterized by early contracture of the elbows, Achilles tendons and post-cervical muscles, slow progressive muscle wasting and weakness and cardiomyopathy presenting with arrhythmia and atrial paralysis: heart block can eventually lead to sudden death. The EDMD geneencodes a novel ubiquitous protein, emerin, which decorates the nuclear rim of many cell types. Amino acid sequence homology and cellular localization suggested that emerin is a member of the nuclear lamina-associated protein family. These findings did not explain the role of emerin nor account for the skeletal muscle- and heart-specific clinical manifestations associated with the disorder. Now we report that emerin localizes to the inner nuclear membrane, via its hydrophobic C-terminal domain, but that in heart and cultured cardiomyocytes it is also associated with the intercalated discs. We propose a general role for emerin in membrane anchorage to the cytoskeleton. In the nuclear envelope emerin plays a ubiquitous and dispensable role in association of the nuclear membrane with the lamina. In heart its specific localization to desmosomes and fasciae adherentes could account for the characteristic conduction defects described in patients.
Hum Mol Genet 1997 Dec
PMID:Heart-specific localization of emerin: new insights into Emery-Dreifuss muscular dystrophy. 936 Oct 31

Emery-Dreifuss muscular dystrophy (EMD) is an X-linked disorder characterized by contractures, progressive weakness and cardiomyopathy. EMD is caused by mutations in the 2 kb emerin gene that is located within human Xq28. Emerin is immediately distal to the 26 kb filamin gene, and flanking the filamin-emerin region are two large inverted repeats. This entire region previously has been found to be inverted in approximately 20% of X chromosomes, presumably mediated by the inverted repeats. Only one complete emerin deletion has been reported previously. It was found to be due to a complex rearrangement involving the inverted repeats which partially duplicated filamin. We report here two additional EMD patients who have large deletions of 20 and 34 kb, respectively. Unlike the previously reported deletion, these deletions appear to be simple deletions, with each breakpoint junction showing only 2 bp of overlap, suggesting an end-joining mechanism. However, the two deletions were found on each of the two inverted backgrounds. The 20 kb deletion includes the entire emerin gene and extends well into most of the distal inverted repeat. In contrast, the 34 kb deletion occurs on the inverted X chromosome and extends centromeric, well beyond the proximal inverted repeat. In addition, at least three nearby putative genes detected by previous sequence analysis are deleted among these patients but without obvious deviation from a typical EMD phenotype. Similarly to the previously reported deletion, filamin remains intact in these two deletions. All three deletions involve distinct breakpoints within the 4.7 kb filamin-emerin intergenic region, suggesting that loss of filamin is a lethal event. Thus, the close proximity of filamin to emerin may place constraints upon potential emerin deletions and probably accounts for the rarity of complete emerin deletions in EMD patients.
Hum Mol Genet 1998 Jan
PMID:Emerin deletions occurring on both Xq28 inversion backgrounds. 938 14


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