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)

Idiopathic dilated cardiomyopathy (DCM) is characterised by a severe dysfunction of the heart muscle resulting in terminal heart failure. Its pathogenesis is believed to be multifactorial involving genetic predisposition, viral infection and autoimmunity, but little is known in detail, and there is no curative treatment except transplantation. Interleukin-1 (IL-1) mediates inflammatory responses to infection and injury. It can be produced by several widely-distributed cell types, including macrophages, and is thought to depress myocyte contractility by stimulating nitric oxide synthase. To investigate whether this pro-inflammatory cytokine may be a pathogenic mediator in DCM, IL-1beta mRNA and protein were evaluated in coronary arteries and myocardium from patients undergoing cardiac transplantation for DCM.IL-1beta mRNA was detected by PCR of cDNA and northern blots of mRNA in coronary arteries and myocardium from patients with DCM. By comparison, samples from patients with ischaemic heart disease (IHD) contained much less IL-1beta mRNA. In contrast, mRNA for other cytokines (TNFalpha, IL-6, IL-10, PDGFA) were similar in both pathologies. In DCM, IL-1beta mRNA and protein were localised to infiltrating macrophages in interstitial regions between myocytes, some of the myocytes themselves, and endothelial cells of vessels in the wall of the arteries. These results suggest that local production of the pro-inflammatory cytokine, IL-1beta may play a part in the pathogenesis of DCM.
J Mol Cell Cardiol 1998 Feb
PMID:Interleukin-1 in myocardium and coronary arteries of patients with dilated cardiomyopathy. 951 98

The study was designed to characterize the relationship between the metabolite content of human cardiac muscle and in vivo cardiac function. ATP, total adenine nucleotides, and NAD were quantified in human myocardial biopsies using high performance liquid chromatography. Right ventricular endomyocardial biopsies were obtained from 43 patients with dilated cardiomyopathy, 6 with restrictive cardiomyopathy, 10 with normal systolic and diastolic function, and from 24 cold preserved human donor hearts. Transmural samples of failing right and left ventricular free walls were obtained during cardiac transplantation surgery in 8 patients. ATP, total adenine nucleotides, and NAD were similar in the cold-preserved donor hearts and in right ventricular endomyocardial biopsies from the 10 individuals with normal systolic and diastolic function. In contrast, these values were significantly depressed in tissue samples from patients with dilated or restrictive cardiomyopathy. There was a significant correlation between ATP and pulmonary capillary wedge pressures but not ejection fractions. Declines in the sizes of myocardial ATP, adenine nucleotide, and pyridine nucleotide pools in the human myocardium are associated primarily with diastolic but not systolic dysfunction.
Mol Cell Biochem 1998 Mar
PMID:Human myocardial ATP content and in vivo contractile function. 954 44

Microtubules of cardiac myocytes are increased in pressure-overloaded cardiac hypertrophy, which interfere with the actin-myosin crossbridge motion and depress muscle contractility. However, it is unknown whether microtubules are increased in non-hypertrophied, dilated cardiomyopathy and, if so, their increase could contribute to the depressed contractility. We assessed the contractile function of isolated left-ventricular (LV) myocytes and also quantitated tubulin mRNA levels as well as free and polymerized tubulin proteins using the LV myocardium obtained from dogs with rapid pacing (240 beats/min, 4 weeks)-induced dilated failing cardiomyopathy (HF; n = 6) and control dogs (n = 6). Myocyte contractility was significantly depressed in HF compared to control. Northern blot analysis indicated that tubulin mRNA levels (normalized to GAPDH mRNA) in HF dogs were upregulated (0.43 +/- 0.04 v 0.13 +/- 0.02; P < 0.01). In contrast, the amount of total tubulins (633 +/- 52 v 697 +/- 42 micrograms/g wet weight; P = N.S.) and the ratio of polymerized tubulin fraction-to-total tubulin (0.44 +/- 0.02 v 0.44 +/- 0.01; P = N.S.) did not differ between the two groups. Immunohistochemical studies showed no apparent differences in the distribution or density of intracellular microtubule network. Further, the exposure of myocytes to colchicine (1 mumol/l, 30 min), which depolymerizes microtubules, did not promote any improvement of the depressed myocyte contraction. Pacing-induced tachycardia increased myocardial tubulin mRNA, but the amount of total and polymerized tubulins were not increased, indicating that alterations in myocyte microtubules do not contribute to the contractile abnormalities in this model of HF.
J Mol Cell Cardiol 1998 May
PMID:Role of microtubules in the contractile dysfunction of myocytes from tachycardia-induced dilated cardiomyopathy. 961 45

The enhanced diastolic Ca2+ levels observed in cardiac myocytes from patients with idiopathic dilated cardiomyopathy (DCM) may be either a consequence of functional impairment of sarcoplasmic reticulum calcium-ATPase (SERCA 2) and its regulator protein phospholamban or due to a reduction in the number of SERCA 2 proteins. As different myocardial membrane preparations may lead to different accumulation of proteins, the present study evaluated two different membrane preparations, in human failing and nonfailing myocardium for comparison of SERCA 2 activity and the protein expression of SERCA 2 and phospholamban. Crude membranes and tissue homo-genates without any centrifugation steps were prepared from human nonfailing hearts (donor hearts, NF, n=18) and terminally failing hearts (heart transplant, DCM, n=18). Calsequestrin protein expression was used as an internal control for overall protein expression. In both crude membranes and homogenates maximal SERCA 2 activity (Vmax) was significantly reduced in failing heart preparations (NF crude membranes, 130+/-8; DCM crude membranes, 102+/-5 nmol ATP/mg protein per minute). In contrast, the protein expression of SERCA 2 (NF crude membranes, 488+/-35; DCM crude membranes, 494+/-42; P=0.92), phospholamban (NF crude membranes, 497+/-51; DCM crude membranes, 496+/-45; P=0.98) and calsequestrin (NF crude membranes, 109+/-06; DCM crude membranes, 107+/-08; P=0.84) was unchanged in NF and DCM hearts in both preparation methods. This was also the case when the protein expression was normalized to calsequestrin protein levels. Preparation of sarcoplasmic reticulum in crude membranes led to enhanced purification and consequently higher SERCA 2, phospholamban, and calsequestrin protein levels in crude membranes than in the homogenates, which was paralleled by an increase in SERCA 2 enzyme activity. In conclusion, the altered Ca2+ handling in DCM may be a consequence of reduced SERCA 2 enzyme activity and not the result of differences in protein expression of the Ca2+ regulating proteins SERCA 2, phospholamban, and calsequestrin in human myocardium. The present study emphasizes the importance of different myocardial membrane preparations with respect to quantitative investigations of protein expression and function.
J Mol Med (Berl) 1998 May
PMID:Unchanged protein expression of sarcoplasmic reticulum Ca2+-ATPase, phospholamban, and calsequestrin in terminally failing human myocardium. 962

The inducible nitric oxide (NO) synthase (iNOS or NOS2) generates a prolonged release of large amounts of NO which may be cytotoxic and/or inhibit myocyte contractility. It has been suggested that this mechanism specifically contributes to heart failure caused by dilated cardiomyopathy (DCM). To test this hypothesis we compared the myocardial amount and localization of iNOS in myocardial biopsies from patients with heart failure caused by either DCM or ischemic heart disease (IHD). During heart transplantation, myocardial biopsies collected from the diseased heart after explantation were frozen in liquid nitrogen. Twenty-two patients in NYHA class III-IV were included (DCM: n = 8; IHD: n = 14). In each biopsy, iNOS expression was assessed using reverse transcription polymerase chain reaction (RT-PCR), and visualized by immunohistochemistry. iNOS was detected in all biopsies. Intriguingly, the amount of iNOS mRNA (shown as iNOS cDNA normalized to GADPH cDNA) did not differ significantly between the two groups (DCM 30 +/- 7; IHD 20 +/- 6, mean +/- S.E.M., P > 0.05). Similarly, no inter-group differences in the amount of iNOS protein (Western) were observed. iNOS was invariably located to vascular endothelial and smooth muscle cells. In addition, an iNOS reaction in relation to the myocyte membrane was found in 4 of the 22 patients. These four patients (two from each group) had significantly (P < 0.05) higher iNOS/GADPH ratios (54 +/- 20) than patients without myocyte membrane iNOS reaction (17 +/- 15). In conclusion, iNOS is expressed in the myocardium of all patients with heart failure caused by either DCM or IHD. iNOS is located primarily and invariably in the endothelium and vascular smooth muscle cells of the myocardial vasculature and its expression appears to be associated with the condition of heart failure per se rather than related to the heart failure etiology.
J Mol Cell Cardiol 1998 Jun
PMID:Inducible nitric oxide synthase (iNOS) in the human heart: expression and localization in congestive heart failure. 968 95

During cardiac hypertrophy and in the failing heart, the chief myocardial energy substrate switches from fatty acids to glucose. In this review, we describe recent progress in the elucidation of the molecular regulatory events involved in the dramatic downregulation of the expression of fatty acid utilization enzymes during development of cardiac hypertrophy and failure. Much of this work has focused on the gene encoding medium-chain acyl-CoA dehydrogenase (MCAD), which catalyzes a pivotal step in the mitochondrial fatty acid -oxidation (FAO) cycle. In vivo ventricular pressure overload studies performed in mice transgenic for human MCAD promoter fragments linked to reporter genes have shown that transcription is markedly downregulated within seven days of pressure overload. The temporal pattern of this alteration in MCAD gene expression has also been characterized in a rat model of progressive pressure overload-induced left ventricular hypertrophy (LVH) and heart failure (HF) [SHHF/Mcc-facp (SHHF) rat]. MCAD mRNA levels are downregulated (>70%) during both the LVH and HF stages in the SHHF rats compared with controls. In contrast, the activity and immunodetectable levels of MCAD enzyme were not significantly reduced until the HF stage, indicating additional compensatory control at the translational or post-translational levels in the hypertrophied but non-failing ventricle. FAO enzyme expression was also shown to be downregulated in human subjects with dilated cardiomyopathy compared to age-matched controls. Taken together, these results have identified a gene regulatory program that is involved in the alterations in myocardial energy substrate utilization in the failing heart. The temporal correlation of diminished enzyme expression with onset of heart failure suggests that this alteration in lipid metabolism may play a role in the pathogenesis of pressure-overload induced heart failure. This gene regulatory pathway should be a useful target for experimental studies aimed at the molecular pathogenesis of the transition from stable cardiac hypertrophy to overt heart failure.
Int J Mol Med 1998 Jan
PMID:The energy substrate switch during development of heart failure: gene regulatory mechanisms (Review). 985 94

A 2-year-old female was well until 12 months of age when she was found to be anemic and had dilated cardiomyopathy. Total plasma carnitine was 6 microM and acylcarnitine analysis while receiving carnitine supplement revealed an increase in the four-carbon species. Urine organic acids were normal. In vitro analysis of the mitochondrial pathways for beta oxidation, and leucine, valine, and isoleucine metabolism was performed in fibroblasts using stable isotope-labeled precursors to these pathways followed by acylcarnitine analysis by tandem mass spectrometry. 16-2H3-palmitate was metabolized normally down to the level of butyryl-CoA thus excluding SCAD deficiency. 13C6-leucine and 13C6-isoleucine were also metabolized normally. 13C5-valine incubation revealed a significant increase in 13C4-isobutyrylcarnitine without any incorporation into propionylcarnitine as is observed normally. These same precursors were also evaluated in fibroblasts with proven ETF-QO deficiency in which acyl-CoA dehydrogenase deficiencies in each of these pathways was clearly identified. These results indicate that in the human, there is an isobutyryl-CoA dehydrogenase which exists as a separate enzyme serving only the valine pathway in addition to the 2-methyl branched-chain dehydrogenase which serves both the valine and the isoleucine pathways in both rat and human.
Mol Genet Metab 1998 Dec
PMID:Isolated isobutyryl-CoA dehydrogenase deficiency: an unrecognized defect in human valine metabolism. 988 13

Duchenne muscular dystrophy (DMD) is caused by a defect in a 427-kDa membrane-associated protein: dystrophin. The DMD gene also encodes several shorter isoforms which are believed to participate in nonmuscle manifestations of DMD, including abnormal retinal electrophysiology, dilated cardiomyopathy, mental retardation, and hearing defects. The purpose of this work was to determine the normal tissue expression of full-length dystrophin (Dp427) and the dystrophin isoforms Dp260, Dp140, Dp116, and Dp71, to aid in understanding what roles these isoforms might play in DMD nonmuscle manifestations. RT-PCR was performed on mRNA isolated from wild-type C57BL/6J mouse tissues, including brain, cardiac muscle, eye, intestine, kidney, liver, lung, skeletal muscle, spleen, stomach, testis, thymus, and uterus. RT-PCR amplification demonstrated that the isoforms were in a number of tissues which had not been revealed by previous Western and Northern blot analyses. Dp427 was expressed at equal levels in all tissues. Dp260 and Dp140 were present in all tissues tested, but the levels of expression varied. Dp116 was expressed in a subset of tissues and levels of expression varied. Dp71 was constitutively expressed in all tissues, suggesting that this isoform plays a basic role in normal tissue function. The expanded tissue distribution supports the hypothesis that dystrophin isoforms serve essential and unique functions, necessitating further investigation into their potential roles in DMD nonmuscle manifestations.
Mol Genet Metab 1998 Dec
PMID:Redefinition of dystrophin isoform distribution in mouse tissue by RT-PCR implies role in nonmuscle manifestations of duchenne muscular dystrophy. 988 14

The purpose of the present study was to investigate the expression and functional relevance of sarcolemmal L-type Ca2+-channels in failing and non-failing human myocardium. The protein expression of sarcolemmal L-type Ca2+-channels was determined with 3H-(+)-PN 200-110-binding experiments and Western blot analysis using a specific antibody against the alpha1-subunit in membrane preparations of ventricular and atrial myocardium from both failing (n = 15) and non-failing hearts (n = 8). The gene expression of the ion conducting pore of the L-type Ca2+-channel was examined with Northern blot technique in human failing and non-failing RNA. For normalization the RNA expression of calsequestrin was used. In electrically driven ventricular papillary muscle strips and auricular trabeculae, the responses to nifedipine and Ca2+ as parameters of myocardial function were studied. The protein expression as measured by 3H-(+)-PN 200-110-binding (Bmax) and Western Blot analysis with calsequestrin as reference was similar in left ventricular failing and non-failing myocardium. However, both were reduced in atrial compared to ventricular tissue in failing and non-failing hearts. The KD remained unchanged. Calsequestrin levels were unaltered in failing and non-failing hearts. The gene expression of the alpha1-subunit was similar in human failing and non-failing hearts. The L-type Ca2+-channel antagonist nifedipine reduced force of contraction with the same potency and efficiency in ventricular failing and non-failing myocardium. In contrast, the potency of nifedipine was higher in atrial than in ventricular tissue. Consistently, atrial myocardium from patients with dilated cardiomyopathy was more sensitive towards Ca2+ than those of the control group. In conclusion, the altered Ca2+-homeostasis in failing human myocardium may be less due to changes in sarcolemmal L-type Ca2+-channel expression or function than due to an altered intracellular Ca2+-handling.
J Mol Cell Cardiol 1999 Jan
PMID:Regional expression and functional characterization of the L-type Ca2+-channel in myocardium from patients with end-stage heart failure and in non-failing human hearts. 1007 35

The intercalated disc is an extremely important specialised structure of cardiac muscle. Intercalated disc alterations have been implicated in ischemic and dilated cardiomyopathy. With a chronic aortic stenosis guinea pig model, we demonstrated in the current study substantial intercalated disc remodeling during the progression of compensated left ventricular (LV) hypertrophy to congestive left heart failure. For the first time, we reported that although the abundance of beta-catenin and vinculin remained unchanged as shown by quantitative Western blotting, the normal distribution of beta-catenin and vinculin at intercalated disc sites was relocated into the cell body in a large fraction of LV myocytes. gamma-Catenin did not show a compensatory up-regulation at the intercalated disc sites where beta-catenin concentration was reduced. Both abundance and distribution of the transmembrane protein N-cadherin remained unchanged in this model. While co-labeled N-cadherin remained unchanged, quantitative confocal microscopy shows that the amount of connexin43 per LV myocyte decreased by 37% at the congestive heart failure stage but not at the compensated hypertrophy stage. No compensatory upregulation of connexin45 was evident when connexin43 was decreased in failing LV myocytes. The relocation of beta-catenin and vinculin away from intercalated discs in failing myocytes may impair the mechanical linkage between N-cadherin and thin filaments and adversely affect myocyte shape. Loss of connexin43 in LV myocytes may impair electrical coupling of adjacent myocytes.
J Mol Cell Cardiol 1999 Feb
PMID:Chronic pressure overload cardiac hypertrophy and failure in guinea pigs: III. Intercalated disc remodeling. 1009 46


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