Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Human hearts with idiopathic dilated cardiomyopathy have diminished adenylate cyclase activity and increased amounts of the alpha-subunit of the inhibitory guanine nucleotide-binding regulatory protein (alpha Gi) as measured by pertussis toxin catalyzed ADP-ribosylation. We utilized specific antisera against synthetic peptides corresponding to amino sequences deduced from cDNA's encoding the three alpha Gi subspecies to compare the immunologic and bioactivity levels of Gi in failing and non-failing human hearts. The various antisera detected three peptides with Mr 42,000, 38,000, and 37,000. Only the Mr 42,000 peptide co-migrated with the pertussis toxin substrate. Although functional activity of alpha Gi was increased in the particulate fractions of the failing heart as measured by inhibition of guanine nucleotide-stimulated adenylate cyclase activity and the quantity of pertussis toxin substrate was also increased, there were not associated changes in the levels of immunodetectable Gi. Therefore, the increased functional activity of Gi in the failing human heart as assessed by adenylate cyclase measurements cannot be explained by a relative increase in the among of Gi protein.
J Mol Cell Cardiol 1991 Apr
PMID:Immunodetectable levels of the inhibitory guanine nucleotide-binding regulatory proteins in failing human heart: discordance with measurements of adenylate cyclase activity and levels of pertussis toxin substrate. 194 80

In the present study, the Ca2(+)-sensitivity and myosin light chain patterns of skinned fibers of right atrium and left papillary muscles of 27 patients suffering from mitral valve disease (MVD, moderate heart failure), ischemic cardiomyopathy (ICM, severe heart failure), dilated cardiomyopathy (DCM, severe heart failure), and coronary heart disease (CHD, no heart failure, no atrial hypertrophy) were investigated. Myosin light chains of both chemically skinned and intact samples were studied by two-dimensional gel electrophoresis (2D-PAGE). Ca2(+)-sensitivity of ventricular fibers was about 0.14 pCa-units higher than that of atrial fibers in all groups except dilated cardiomyopathy where this difference was markedly diminished (only 0.06 pCa-units). Generally, Ca2(+)-sensitivity of skinned ventricular fibers was the same among the different heart diseases. Skinned atrial fibers from patients with dilated cardiomyopathy, however, were significantly (about 0.08 pCa-units) more sensitive for Ca2+ than those of the other groups (coronary heart disease, mitral valve disease or ischemic cardiomyopathy) which showed similar Ca2(+)-tension relationships. Ventricle-specific P-light chain forms could be observed in atrial samples from patients of all groups, whereas no atrium-specific light chain forms were detectable in any ventricular sample. It is concluded that there is no difference in Ca2(+)-sensitivity of the ventricular contractile elements of the human heart in different heart diseases. In atrial myocardium, there is an increased Ca2(+)-sensitivity of skinned fibers from hearts with dilated cardiomyopathy which is probably related to an elevation of right atrial pressure.
J Mol Cell Cardiol 1990 Dec
PMID:Calcium sensitivity and myosin light chain pattern of atrial and ventricular skinned cardiac fibers from patients with various kinds of cardiac disease. 208 58

Monoclonal and polyclonal antibodies to the major sarcoplasmic reticulum proteins of rabbit skeletal and canine cardiac muscle have been used to identify and characterize the corresponding components of human cardiac sarcoplasmic reticulum. The Ca2(+)-transporting ATPase of human cardiac sarcoplasmic reticulum was identified as a 105,000-Da protein antigenically distinct from its rabbit skeletal muscle counterpart. Human cardiac sarcoplasmic reticulum also contained 53,000- 155,000- and 165,000-Da glycoproteins antigenically related to the low and high molecular weight glycoproteins of canine cardiac and rabbit skeletal muscle sarcoplasmic reticulum. The ryanodine-sensitive Ca2+ channel of human cardiac sarcoplasmic reticulum was identified as a 400,000-Da protein antigenically related to its counterparts in canine cardiac and rabbit skeletal muscle. Human cardiac calsequestrin was identified as a 52,000-Da protein. Human phospholamban was identified as a 29,000-Da substrate for phosphorylation by cAMP-dependent protein kinase. Immunoblots of sarcoplasmic reticulum from the normal left ventricles of four unmatched organ donors and the excised failing left ventricles of nine patients with idiopathic dilated cardiomyopathy were compared in search of qualitative differences in the protein patterns of the failing hearts. No such differences were found with respect to the Ca2+ ATPase, the 53,000-Da glycoprotein, the ryanodine-sensitive Ca2+ channel, calsequestrin or phospholamban. In contrast, the 165,000-Da glycoprotein band, present in all four preparations from nonfailing hearts, was absent from three of nine preparations from failing hearts, and staining of the 155,000-Da glycoprotein in these three preparations appeared to be relatively increased. The absence of the 165,000-Da glycoprotein band may identify or reflect a pathogenetic mechanism in a subset of patients with idiopathic dilated cardiomyopathy.
J Mol Cell Cardiol 1990 Dec
PMID:Identification and characterization of proteins in sarcoplasmic reticulum from normal and failing human left ventricles. 208 60

We have recently demonstrated that the activity of the inhibitory guanine nucleotide-binding regulatory protein Gi is increased in the hearts of patients with idiopathic dilated cardiomyopathy. We determined whether altered Gi protein levels in the failing human heart correlate with changes in steady state levels of the mRNA encoding one of the alpha Gi peptides. cDNAs encoding alpha Gs, alpha Go, and three subspecies of alpha Gi were used as hybridization probes to quantify steady state levels of mRNA encoding these alpha G peptides in failing and non-failing human heart. The lengths of the mRNAs that encode each alpha G peptide were the same in non-failing and failing hearts. Steady state levels of mRNA encoding both alpha Gi-3 and alpha Gs were significantly increased in the failing hearts when compared to non-failing hearts. By contrast, there was no significant change in the levels of mRNA encoding alpha Go or of rRNA. The relative abundance of the mRNA encoding each of the subspecies of alpha Gi was different in the human heart; alpha Gi-3 mRNA was abundant, alpha Gi-2 was barely detectable, and we were not able to detect alpha Gi-1 utilizing our hybridization conditions. These results suggest that alterations at the level of transcription as well as post-translational modifications can affect the activities of transmembrane signaling proteins in chronic congestive heart failure.
J Mol Cell Cardiol 1989 Apr
PMID:Altered expression of alpha-subunits of G proteins in failing human hearts. 250 99

Dermatopathic lymphadenitis is a non-neoplastic lesion found with various chronic skin lesions and associated with hyperplasia of the thymus-dependent (T) areas. These areas consist chiefly of interdigitating reticulum cells (IDC's), which are known to be accessory cells for T-cell-dependent immune reactions. The most characteristic features of IDC's are the bizarre-shaped cell nucleus, numerous cytoplasmic processes, deep cytoplasmic invaginations, and a close topographical relationship to surrounding (T) lymphocytes. The cytoplasmic processes of IDC's do not interdigitate with adjacent lymphocytes, as previously reported in the literature, but show close interdigitations with the processes of neighboring IDC's. With the freeze-fracture technique it can be seen that IDC's exhibit a characteristic distribution of intramembranous particles (IMP). While, for example, macrophages, epithelioid cells and lymphocytes display a clearly greater number of IMP on the P face than on the E face, IDC's show an equally high particle density on both the P face and the E face. The organelle content of IDC's in dermatopathic lymphadenitis varies considerably. Tubular profiles, the Golgi apparatus and vesicles may be increased in number. Birbeck granules are also found in IDC's, but only rarely. Variations in the numbers of the different cytoplasmic organelles may be a reflection of varying degrees of metabolic activity of IDC's.
Virchows Arch B Cell Pathol Incl Mol Pathol 1988
PMID:Interdigitating reticulum cells in dermatopathic lymphadenitis: freeze-fracture and ultrathin-section morphology. 289 30

Eleven axillary lymph nodes from patients with different cutaneous disorders (systemic scleroderma, atopic eczema, psoriasis, hairy cell erythroderma, dermatopathic lymphadenitis) were examined by electron microscopy. In systemic scleroderma interdigitating cells (IDC's) showed typical ultrastructural features as well as intimate contacts with neighboring lymphocytes. In atopic eczema IDC's were characterized by widespread invaginations of the cell membrane, and an increase in tubulo-vesicular structures and microfilaments. Similar observations have been made in dermatopathic lymphadenitis. In psoriasis and hairy cell erythroderma. IDC's showed only a few interdigitations and invaginations of the cell surface. It is supposed that these structural changes in IDC's reflect the different immunological conditions of the diverse cutaneous disorders.
Virchows Arch B Cell Pathol Incl Mol Pathol 1980
PMID:Ultrastructural differences of interdigitating cells in human lymph nodes. 610 48

Histiocytic (HRC) and interdigitating (IDC) reticulum cells were obtained from human lymphoid tissue (lymph nodes, tonsils), suspended in cell culture medium and cultured. The suspended cells, which were identified by morphological and enzyme histochemical criteria, were studied for surface binding properties for Fc-receptors using erythrocytes coated with IgG. HRC show strong surface binding, IDC, somewhat weaker, but definitely positive surface binding. Both types of reticulum cells possess Fc-receptors; on IDC, however, they are fewer in number and less dense. In connection with recently discovered Fc-receptors on Langerhans cells of the epidermis, functional relationships between blood monocytes, Langerhans cells in skin and IDC in lymphoid tissue are discussed.
Virchows Arch B Cell Pathol Incl Mol Pathol 1981
PMID:Functional studies on histiocytic and interdigitating reticulum cells from human lymphoid tissue. 611 9

Angiotensin I-converting enzyme (ACE) is responsible for the production of angiotension II and the breakdown of kinins, leading to increased blood pressure (BP), induction of vascular smooth muscle cell proliferation, and the stimulation of myocardial-cell hypertrophy. A 287 bp insertion/deletion polymorphism in intron 16 of the ACE gene was examined by polymerase chain reaction in a cross-sectional study of 35 patients with idiopathic dilated cardiomyopathy (IDC) and 35 patients with normally functioning hearts (NT). Compared with the deletion/deletion (D/D) frequency in the control population, the frequency of the deletion allele was 0.757 in IDC patients and 0.600 in NTs; the difference between observed alleles in all subjects in each group was significant (x2 = 3.96; P < 0.05). The data thus provide evidence in favor of an association between idiopathic dilated cardiomyopathy and a polymorphism at the ACE locus (17q23), thus implicating this locus, and possibly a genetic variant of ACE, itself, in human idiopathic dilated cardiomyopathy.
Biochem Mol Biol Int 1995 May
PMID:Evidence that polymorphism of the angiotensin I converting enzyme gene may be related to idiopathic dilated cardiomyopathy in the Chinese population. 749 54

In a preceding communication (Wallukat et al., 1992, Z Kardiol 81 [Suppl. 4]: 79-83), it was reported that synthetic peptides, corresponding in amino acid sequence to either the first or the second extracellular loop of the human beta 1-adrenoceptor, selectively suppressed the metoprolol- and bisoprolol-sensitive positive chronotropic action exerted in cultures of beating neonatal rat cardiomyocytes by the serum immunoglobulin fraction of patients with myocarditis and idiopathic dilated cardiomyopathy (DCM) and by affinity-purified autoantibodies from that fraction. These observations added to existing evidence that these antibodies were directed against the beta 1-adrenoceptor and might thus contribute to the harmful chronic cardiac adrenergic drive to which patients with DCM are believed to be exposed. Specifically, they pointed to the putative first and second extracellular loops of this receptor (these loops are each identical in man and the rat) as the sites of epitopes recognized by the chronotropically active, beta 1-agonistic autoantibodies. Now we report on the mapping of these epitopes with the help of two series of short synthetic overlap peptides, one series forming part of the first and the other of the second extracellular loop of the beta 1-adrenoceptor. Inhibition of the positive chronotropic response of cultured rat cardiomyocytes to the anti-beta 1-receptor autoantibodies (EC50 = 0.14 +/- 0.01 nM) from the serum immunoglobulin fraction of patients with DCM was taken as reflecting the neutralization of these antibodies by a particular overlap peptide. In this way the sequences S-F-F-C-E-L (residues 129-134) and A-R-R-C-Y-N-D (residues 206-212) emerged as the dominant epitopes in the first and second extracellular loops, respectively, followed with respect to neutralizing ability by the first loop sequence E-Y-G-S-F-F (residues 126-131) and the second loop sequences H-W-W-R-A-E (residues 197-202) and P-K-C-C-D-F (residues 213-218). Synthetic peptides corresponding to the sequences of the third extracellular loop of the beta 1-receptor (residues 346-356) and of the second extracellular loop of the human beta 2-receptor (residues 172-197) failed to neutralize the beta 1-agonistic autoantibodies. Using dithiothreitol as a reducing agent a disulfide bridge between cysteine 132 in the first and cysteine 209 in the second extracellular loop was considered to be essential for the chronotropic action of these autoantibodies.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Cell Cardiol 1995 Jan
PMID:Anti-beta 1-adrenoceptor autoantibodies with chronotropic activity from the serum of patients with dilated cardiomyopathy: mapping of epitopes in the first and second extracellular loops. 753 84

End stage heart failure due to ischemic (ICM) or dilated (DCM) cardiomyopathy is characterized by a dilated, relatively thin-walled ventricle. The hypothesis has been proposed that the structural basis of ventricular expansion is due to side-to-side slippage of myocytes within the wall. Although this represents one potential mechanism for the observed phenomena of chamber dilatation and subsequent wall thinning, the degree of slippage claimed is not necessarily in harmony with the magnitude of chamber enlargement and mural thinning. Moreover, sarcomere extension was not examined in the base to the apical regions of the heart, leaving open the question as to the role of changes in resting sarcomere length in acute chamber dilatation. In this regard, an alternative etiology for the detrimental cardiac architectural rearrangement seen in dilated failure can be supplied by postulating the occurrence of maladaptive remodeling of cardiac myocyte morphology. In this model, myocytes increase in length by an increase in the number of sarcomeres in series, thus increasing chamber diameter in an attempt to maintain cardiac output. However, these cells do not enlarge to any significant degree in the transverse diameter preventing the heart from developing adequate force. This hypothesis is supported by recent evidence from patients with ICM and DCM indicating that myocyte lengthening alone could account for all the dilatation observed. Furthermore, it appears that the thinning of the ventricular wall in failure is due to inadequate transverse growth of cardiac myocytes coupled with scattered myocyte cell loss throughout the ventricular wall.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1995 Mar
PMID:Structural remodeling and mechanical dysfunction of cardiac myocytes in heart failure. 760 3


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