Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We made quantitative measurements of phosphorylation in troponin isolated from 6 non-failing donor hearts and 6 explanted hearts with end-stage heart failure in SDS-PAGE gels using Pro-Q Diamond phosphoprotein stain. The troponin T phosphorylation level was the same in troponin from failing and non-failing heart (3.1 mol Pi/mol). However, troponin I phosphorylation was significantly lower in failing (0.37+/-0.18 mol Pi/mol) compared with non-failing heart troponin (2.25+/-0.36 mol Pi/mol). Levels of troponin I PKA-dependent phosphorylation, measured with a phosphoserine 23/24-specific antibody, were also significantly lower in failing heart troponin (0.19+/-0.06 mol Pi/mol) compared to non-failing troponin (1.14+/-0.09 mol Pi/mol). We calculate that there is phosphorylation in addition to serine 23/24 of 1.11+/-0.34 mol Pi/mol in non-failing reduced to 0.18+/-0.17 mol Pi/mol in failing heart troponin, attributed to phosphorylation on the PKC sites. To test for the functional role of troponin I phosphorylation, the native troponin I from either non-failing or failing heart troponin was exchanged for a recombinant (unphosphorylated) human cardiac troponin I. Thin filament Ca(2+)-regulatory function was studied with the quantitative in vitro motility assay: thin filaments containing the replaced troponin I resulted in a failing phenotype of a 17-26% reduced sliding speed and an increased Ca(2+)-sensitivity relative to non-failing troponin (EC(50) TnI-exchanged/non-failing=0.57, p<0.001). When exchanged with troponin I phosphorylated with PKA motility parameters reverted to a pattern indistinguishable from non-failing troponin (p=0.35-0.75). We suggest that changes in troponin function can account for the contractile abnormality in failing heart muscle and that the functional changes in troponin are due to reduced phosphorylation of troponin I at the PKA sites.
 ...
PMID:Troponin phosphorylation and regulatory function in human heart muscle: dephosphorylation of Ser23/24 on troponin I could account for the contractile defect in end-stage heart failure. 1708 61

Heart failure is associated with a skeletal muscle myopathy with cellular and extracellular alterations. The hypothesis of this investigation is that extracellular changes may be associated with enhanced mRNA expression and activity of matrix metalloproteinases (MMP). We examined MMP mRNA expression and MMP activity in Soleus (SOL), extensor digitorum longus (EDL), and diaphragm (DIA) muscles of young Wistar rat with monocrotaline-induced heart failure. Rats injected with saline served as age-matched controls. MMP2 and MMP9 mRNA contents were determined by RT-PCR and MMP activity by electrophoresis in gelatin-containing polyacrylamide gels in the presence of SDS under non-reducing conditions. Heart failure increased MMP9 mRNA expression and activity in SOL, EDL and DIA and MMP2 mRNA expression in DIA. These results suggest that MMP changes may contribute to the skeletal muscle myopathy during heart failure.
 ...
PMID:Heart failure alters matrix metalloproteinase gene expression and activity in rat skeletal muscle. 1722 11

Atrial natriuretic peptide (ANP) and B-type natriuretic peptide decrease blood pressure and cardiac hypertrophy by activating natriuretic peptide receptor A (NPR-A), a transmembrane guanylyl cyclase also known as guanylyl cyclase A. Inactivation of NPR-A is a potential mechanism for the renal hyporesponsiveness observed in congestive heart failure (CHF) but direct data supporting this hypothesis are lacking. We examined whether NPR-A activity was reduced in CHF, and if so, by what mechanism. In two separate trials, CHF was induced in mice by 8-wk transverse aortic constriction. Sham controls underwent surgery without constriction. The constricted animals developed severe heart failure as indicated by increased heart weight, increased left ventricular end diastolic and systolic diameters, and decreased left ventricular ejection fractions. Kidney membranes were assayed for guanylyl cyclase activity or used to purify NPR-A by sequential immunoprecipitation/SDS-PAGE. Maximal ANP-dependent guanylyl cyclase activities were reduced by 44 or 43% in kidney membranes from CHF animals in two independent trials. Basal cyclase activities were also reduced by 31% in the second trial. The amount of phosphorylated NPR-A was reduced by 25 or 24% in kidney membranes from CHF animals as well. SYPRO Ruby staining suggested that NPR-A protein levels were similar between treatments in the first trial. However, more accurate estimates of NPR-A protein levels by immunoprecipitation/Western analysis in the second trial indicated that NPR-A protein was reduced by 30%. We conclude that reduced NPR-A protein levels, not receptor dephosphorylation, explain the renal hyporesponsiveness to natriuretic peptides in CHF.
 ...
PMID:Renal hyporesponsiveness to atrial natriuretic peptide in congestive heart failure results from reduced atrial natriuretic peptide receptor concentrations. 1726 12

Cardiomyocyte apoptosis has an important role in the transition from compensatory cardiac remodeling to heart failure. All-trans retinoic acid (RA), a bioactive vitamin A derivative, prevents stretch- and angiotensin II (Ang II)-induced cardiac hypertrophy. However, the anti-apoptotic potential of RA in the heart remains unexplored. Here, we demonstrate that stretch- and Ang II-induced apoptosis is prevented by RA in neonatal cardiomyocytes. RA improved mitochondrial function by inhibiting the stretch- and Ang II-induced reduction in mitochondrial membrane potential, cytochrome c release and by increasing the Bcl2/Bax ratio. RA inhibited stretch- and Ang II-induced intracellular reactive oxygen species (ROS) generation and upregulated the SOD2 level. Hydrogen peroxide-induced increases in the number of TUNEL-positive cells and percentage of Annexin V positive cells, were dose-dependently inhibited by RA. The thiol antioxidant, N-acetyl cysteine (NAC), completely inhibited stretch- and Ang II-induced apoptosis. Using diazoxide (mitochondrial ATP-sensitive K(+) channel opener) and SDS (NADPH oxidase activator), we confirmed that RA suppressed both mitochondrial- and NADPH oxidase-derived ROS. We also observed that both RAR and RXR were involved in preventing Ang II- and stretch-induced ROS production and apoptosis, by using selective retinoid receptor agonists and antagonists. Our data provide the first evidence that RA prevents Ang II and stretch induced apoptosis, by inhibiting ROS generation and increasing the anti-oxidant defense system, suggesting that RA-mediated signaling may provide a new therapeutic target for the prevention of the cardiac remodeling process.
 ...
PMID:All-trans retinoic acid prevents angiotensin II- and mechanical stretch-induced reactive oxygen species generation and cardiomyocyte apoptosis. 1794 Oct 88

Previous studies have reported that myosin can be modified by oxidative stress and particularly by activated haem proteins. These reactions have been implicated in changes in the properties of this protein in food samples (changes in meat tenderness and palatability), in human physiology (alteration of myocyte function and force generation) and in disease (e.g. cardiomyopathy, chronic heart failure). The oxidant species, mechanisms of reaction and consequences of these reactions are incompletely characterized. In the present study, the nature of the transient species generated on myosin as a result of the reaction with activated haem proteins (horseradish peroxidase/H2O2) and met-myoglobin/H2O2) has been investigated by EPR spectroscopy and amino-acid consumption, product formation has been characterized by HPLC, and changes in protein integrity have been determined by SDS/PAGE. Multiple radical species have been detected by EPR in both the presence and the absence of spin traps. Evidence has been obtained for the presence of thiyl, tyrosyl and other unidentified radical species on myosin as a result of damage-transfer from oxidized myoglobin or horseradish peroxidase. The generation of thiyl and tyrosyl radicals is consistent with the observed consumption of cysteine and tyrosine residues, the detection of di-tyrosine by HPLC and the detection of both reducible (disulfide bond) and non-reducible cross-links between myosin molecules by SDS/PAGE. The time course of radical formation on myosin, product generation and cross-link induction are consistent with these processes being interlinked. These changes are consistent with the altered function and properties of myosin in muscle tissue exposed to oxidative stress arising from disease or from food processing.
 ...
PMID:Oxidation of myosin by haem proteins generates myosin radicals and protein cross-links. 1803 81

The N-terminal fragment of pro B-type natriuretic peptide (NT-proBNP) and proBNP are used as gold standard clinical markers of myocardial dysfunction such as cardiac hypertrophy and left ventricle heart failure. The actual circulating molecular forms of these peptides have been the subject of intense investigation particularly since these analytes are measured in clinical assays. Conflicting data has been reported and no firm consensus on the exact nature of the molecular species exists. Because these clinical assays are immunoassay-based, specific epitopes are detected. It is conceivable then that certain epitopes may be masked and therefore unavailable for antibody binding, thus the importance of determining the nature of the circulating molecular forms of these analytes. This situation is an unavoidable Achilles' heel of immunoassays in general. A recombinant O-linked glycosylated form of proBNP has been show to mimic some of the properties of extracted plasma from a heart failure patient. In particular the recombinant and native material co-migrated as diffuse Western-immunostained bands on SDS-PAGE and each band collapsed to an apparent homogeneous band following deglycosylation. Thus, glycosylated-proBNP may be one such circulating form. Here we provide extensive physiochemical characterization for this O-linked protein and compare these results to other described circulating species, non-glycosylated-proBNP and NT-proBNP. It will be shown that glycosylation has no influence on the secondary and quaternary structure of proBNP. In fact, at moderate concentration in benign physiological neutral pH buffer, all three likely circulating species are essentially devoid of major secondary structure, i.e., are intrinsically unstructured proteins (IUPs). Furthermore, all three proteins exist as monomers in solution. These results may have important implications in the design of NT-proBNP/BNP immunoassays.
 ...
PMID:A glycosylated form of the human cardiac hormone pro B-type natriuretic peptide is an intrinsically unstructured monomeric protein. 1844 Feb 96

Phosphorylation of myosin binding protein C (MyBP-C) was investigated in intraventricular septum samples taken from patients with hypertrophic cardiomyopathy undergoing surgical septal myectomy. These samples were compared with donor heart muscle, as a well-characterised control tissue, and with end-stage failing heart muscle. MyBP-C was partly purified from myofibrils using a modification of the phosphate-EDTA extraction of Hartzell and Glass. MyBP-C was separated by SDS-PAGE and stained for phosphoproteins using Pro-Q Diamond followed by total protein staining using Coomassie Blue. Relative phosphorylation level was determined from the ratio of Pro-Q Diamond to Coomassie Blue staining of MyBP-C bands as measured by densitometry. We compared 9 myectomy samples and 9 failing heart samples with 9 donor samples. MyBP-C phosphorylation in pathological muscle was lower than in donor (myectomy 40+/-2% of donor, P<0.0001; failing 45+/-3% of donor, P<0.0001). 6 myectomy samples were identified with MYBPC3 mutations, one with MYH7 mutation and two remained unknown, but there was no correlation between MYBPC3 mutation and MyBP-C phosphorylation level. In order to determine the number of phosphorylated sites in human cardiac MyBP-C samples, we phosphorylated the recombinant MyBP-C fragment, C0-C2 (1-453) with PKA using (gamma32)P-ATP up to 3.5 mol Pi/mol C0-C2. This measurement of phosphorylation was used to calibrate measurements of phosphorylation in SDS-PAGE using Pro-Q Diamond stain. The level of phosphorylation in donor heart MyBP-C was calculated to be 4.6+/-0.6 mol Pi/mol and 2.0+/-0.3 mol Pi/mol in myectomy samples. We conclude that MyBP-C is a highly phosphorylated protein in vivo and that diminished MyBP-C phosphorylation is a feature of both end-stage heart failure and hypertrophic cardiomyopathy.
 ...
PMID:Myosin binding protein C phosphorylation in normal, hypertrophic and failing human heart muscle. 1857 60

Cardiac troponin I phosphorylation has been shown to be reduced in human heart failure and hypertrophic cardiomyopathy using the increasingly popular Pro-Q Diamond phosphoprotein gel stain. In this brief report I discuss the use of Western immunoblotting, non-equilibrium isoelectric focussing and Pro-Q Diamond and introduce phosphate affinity SDS-PAGE using Phos-tag-acrylamide for the investigation of troponin I phosphorylation.
 ...
PMID:Current techniques for the study of troponin I phosphorylation in human heart. 1917 3

Cachexia is a common syndrome in advanced cancer patients and causes up to 22% of cancer-related deaths. It remains elusive whether cancer cachexia causes heart failure. We investigated the effect of cancer cachexia on heart function and cardiac muscle structure in a mouse model. Male CD2F1 mice were inoculated with either colon-26 adenocarcinoma cells (Tumor group) or vehicle (PBS) (No Tumor group and Pair-fed group). Heart function as measured by fractional shortening in vivo using transthoracic echocardiography was performed on day 14 after tumor or PBS inoculation. At necropsy (day 17), hearts were collected for histology, transmission electron microscopy, RT-PCR and SDS-PAGE analysis. Mice from the Tumor group displayed a significantly reduced fractional shortening compared to mice in the No Tumor and Pair-fed groups. In hearts of the Tumor mice compared to the other groups, there was marked fibrosis and transmission electron microscopy revealed disrupted myocardial ultrastructure. Gene expression of troponin I, a regulator of cardiac muscle contraction, was reduced. Moreover, both mRNA and protein levels of myosin heavy chain (MHC) were altered whereby MHCalpha (adult isoform) was decreased and MHCbeta (fetal isoform) was increased indicating reactivation of the fetal gene expression pattern. In conclusion, heart function was diminished in mice with tumor-induced cachexia, and this impaired function was associated with increased fibrosis, disrupted myocardial structure and altered composition of contractile proteins of cardiac muscle.
 ...
PMID:Cardiac alterations in cancer-induced cachexia in mice. 2059 62

Heart failure (HF) is characterized by limited exercise tolerance, skeletal muscle atrophy, a shift toward fast muscle fiber, and myogenic regulatory factor (MRF) changes. Reactive oxygen species (ROS) also contribute to target organ damage in this syndrome. In this study, we investigated and compared morphofunctional characteristics and gene expression in Soleus (SOL--oxidative and slow twitching muscle) and in Extensor Digitorum Longus (EDL--glycolytic and fast twitching muscle) during HF. Two groups of rats were used: control (CT) and heart failure (HF), induced by a single injection of monocrotaline. MyoD and myogenin gene expression were determined by RT-qPCR, and MHC isoforms by SDS-PAGE; muscle fiber type frequency and cross sectional area (CSA) were analyzed by mATPase. A biochemical study was performed to determine lipid hydroperoxide (LH), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD); myography was used to determine amplitude, rise time, fall time, and fatigue resistance in both muscles. HF showed SOL and EDL muscle atrophy in all muscle fiber types; fiber frequency decreased in type IIC and muscle contraction fall time increased only in SOL muscle. Myogenin mRNA expression was lower in SOL and myoD decreased in HF EDL muscle. LH increased, and SOD and GSH-Px activity decreased only in HF SOL muscle. HF EDL muscle did not present changes in MHC distribution, contractile properties, HL concentration, and antioxidant enzyme activity. In conclusion, our results indicate that monocrotaline induced HF promoted more prominent biochemical, morphological and functional changes in SOL (oxidative and slow twitching muscle). Although further experiments are required to better determine the mechanisms involved in HF pathophysiology, our results contribute to understanding the muscle-specific changes that occur in this syndrome.
 ...
PMID:Differential morphofunctional characteristics and gene expression in fast and slow muscle of rats with monocrotaline-induced heart failure. 2150 45


<< Previous 1 2 3 Next >>