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

We report here that interleukin (IL)-13 protects BALB/c mice from myocarditis, whether induced by peptide immunization or by viral infection. In contrast to mild disease in IL-4 knockout (KO) BALB/c mice, IL-13 KO BALB/c mice developed severe coxsackievirus B3 (CVB3)-induced autoimmune myocarditis and myocarditogenic peptide-induced experimental autoimmune myocarditis. Such severe disease was characterized by increased cardiac inflammation, increased total intracardiac CD45(+) leukocytes, elevated anti-cardiac myosin autoantibodies, and increased cardiac fibrosis. Echocardiography revealed that IL-13 KO mice developed severe dilated cardiomyopathy with impaired cardiac function and heart failure. Hearts of IL-13 KO mice had increased levels of the proinflammatory and profibrotic cytokines IL-1beta, IL-18, interferon-gamma, transforming growth factor-beta1, and IL-4 as well as histamine. The hallmark of the disease in IL-13 KO mice was the up-regulation of T-cell responses. CD4(+) T cells were increased in IL-13 KO hearts both proportionally and in absolute number. Splenic T cells from IL-13 KO mice were highly activated, and myosin stimulation additionally increased T-cell proliferation. CD4(+)CD25(+)Foxp3(+) regulatory T-cell numbers were decreased in the spleens of IL-13 KO mice. IL-13 deficiency led to decreased levels of alternatively activated CD206(+) and CD204(+) macrophages and increased levels of classically activated macrophages. IL-13 KO mice had increased caspase-1 activation, leading to increased production of both IL-1beta and IL-18. Therefore, IL-13 protects against myocarditis by modulating monocyte/macrophage populations and by regulating their function.
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PMID:Interleukin-13 protects against experimental autoimmune myocarditis by regulating macrophage differentiation. 1840 98

TNFalpha is a cytokine wit pleiotropic functions in many organs. In the heart increased TNFalpha levels are not only associated with heart failure, but also, paradoxically, with protection from ischemic damage. To test whether the protective role of TNFalpha in the heart is concentration-dependent, we studied two mouse heart models with low (two- to threefold) over-expression of endogenous TNFalpha: mice deficient in a translational repressor of TNFalpha mRNA, TIA-1(-/-), and mice over-expressing human TNFalpha. Hearts lacking TIA-1 were characterized for their endogenous TNFalpha over-expression during normal Langendorff perfusion. To define which TNFalpha receptor mediates cardiac protection, we also used mice lacking the TNFR1 receptor. Contractile function was assessed in isolated hearts perfused in the isovolumic Langendorff mode during and following global no-flow ischemic stress and in response to varying extracellular [Ca(2+)] to determine their contractile response and Ca(2+) sensitivity. All hearts with low over-expression of TNFalpha, independent of human or murine origin, have improved contractile performance and increased Ca(2+) sensitivity (by 0.2-0.26 pCa). Hearts lacking TNFR1 have contractile performance equal to wild type hearts. Recovery from ischemia was greater in TIA-1(-/-) and was diminished in TNFR1(-/-). Better contractile function in TNFalpha over-expressing hearts is not due to improved cardiac energetics assessed as [ATP] and glucose uptake or to differences in expression of SERCA2a or calmodulin. We suggest that low levels of TNFalpha increase the Ca(2+) sensitivity of the heart via a TNFR1-mediated mechanism.
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PMID:Low over-expression of TNFalpha in the mouse heart increases contractile performance via TNFR1. 1845 58

Dietary copper (Cu) deficiency causes cardiac hypertrophy and its transition to heart failure in a mouse model. Cu repletion results in rapid regression of cardiac hypertrophy and prevention of heart failure. The present study was undertaken to understand dynamic changes of cardiomyocytes in the hypertrophic heart during the regression. Dams of FVB mice were fed a Cu-deficient (CuD) diet (0.3 mg Cu/kg) starting on Day 3 post-delivery, and weanling pups were fed the same diet until Cu repletion (6.0 mg Cu/kg) in the diet at 31 days of age. Heart samples were obtained at the end of CuD feeding or at 3, 7, 14 or 28 days after Cu repletion. Cu deficiency resulted in increases in the size and reduction in the number of cardiomyocytes in the heart. Cu repletion led to regression in the size of hypertrophic cardiomyocytes and normalization of the total number of cardiomyocytes. Although a direct reduction in the cell size would be significantly responsible for the regression of heart hypertrophy, some hypertrophic cardiomyocytes upon Cu repletion reentered the cell cycle as determined by Ki-67 staining in the cardiomyocyte-specific alpha-sarcomeric actin-stained cells and underwent division as determined by a mitosis-specific marker, phospho-histone 3. Quantitative analysis indicated that the replication of hypertrophic cardiomyocytes made a contribution of about one-third to the total mitosis of the regenerated myocardium. This study suggests that a direct reduction in the size of some hypertrophic cardiomyocytes and a replication of other hypertrophic cardiomyocytes with reduced size make a significant contribution to the regression of CuD heart hypertrophy, leading to normalization of the size and the number of cardiomyocytes in the heart.
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PMID:Regression of copper-deficient heart hypertrophy: reduction in the size of hypertrophic cardiomyocytes. 1902 82

Adrenergic regulation of the heart function is well documented by many studies. Catecholamines act through alpha(1)-, beta(1)-, beta(2)-, and beta(3)-adrenoceptors (ARs) in the heart. There are many findings about the changes of beta(1)- and beta(2)-AR in heart failure (HF). On the other hand, the role of other AR subtypes is not clear yet. We focused on determining how HF could affect gene expression and specific ligand binding to alpha(1A)-, alpha(1B)-, alpha(1D)-, beta(1)-, beta(2)-, and beta(3)-AR. Hearts from 11 patients with HF subjected to transplantation were investigated. As a control, corresponding parts from hearts not suitable for transplantation were used. We have found significantly higher mRNA levels of alpha(1A)-, alpha(1B)-,beta(1)-, and beta(2)-AR in the left ventricle of failing hearts compared to the levels in controls. beta(3)-AR mRNA levels in the left ventricle of failing hearts were not changed. No changes in mRNA levels of all receptors studied in other cardiac areas were found. On the other hand, binding studies showed a substantial decrease in left ventricles of failing hearts in all alpha(1)-AR subtypes and in beta(1)- and beta(2)-AR. However, the binding to beta(3)-AR was not changed. Our results suggest that alpha(1)-AR changes might be part of a compensatory mechanism, by which the heart suffering from the HF tries to secure its function, and it could be hypothesized that ineffective beta(3)-AR regulation might be involved in development of HF. According to our knowledge, this is the first report about the beta(3)-AR binding in HF.
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PMID:Heart adrenoceptor gene expression and binding sites in the human failing heart. 1912 Jan 34

Pathological conditions, including ischemia and heart failure, are associated with altered sodium channel function and increased late sodium current (I(Na,L)), leading to prolonged action potential duration, increased intracellular sodium and calcium concentrations, and arrhythmias. We used anemone toxin (ATX)-II to study the effects of increasing I(Na,L) on intracellular calcium cycling in rat isolated hearts. Cardiac contraction was abolished using paralytic agents. Ranolazine (RAN) was used to inhibit late I(Na). Hearts were loaded with fluo-4-acetoxymethyl ester, and myocyte intracellular calcium transients (CaTs) were measured using laser scanning confocal microscopy. ATX (1 nM) prolonged CaT duration at 50% recovery in hearts paced at a basal rate of 2 Hz and increased the sensitivity of the heart to the development of calcium alternans caused by fast pacing. ATX increased the time required for recovery of CaT amplitude following a previous beat, and ATX induced spontaneous calcium release waves during rapid pacing of the heart. ATX prolonged the duration of repolarization from the initiation of the activation to terminal repolarization in the pseudo-electrocardiogram. All actions of ATX were both reversed and prevented by subsequent or prior exposure, respectively, of hearts to RAN (10 microM). Most importantly, the increased vulnerability of the heart to the development of calcium alternans during rapid pacing was reversed or prevented by 10 microM RAN. These results suggest that enhancement of I(Na,L) alters calcium cycling. Reduction by RAN of I(Na,L)-induced dysregulation of calcium cycling could contribute to the antiarrhythmic actions of this agent in both reentrant and triggered arrhythmias.
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PMID:Ranolazine antagonizes the effects of increased late sodium current on intracellular calcium cycling in rat isolated intact heart. 1967 98

The p38 MAP kinases are stress-activated MAP kinases whose induction is often associated with the onset of heart failure. This study investigated the role of p38 MAP kinase isoforms in the regulation of myocardial contractility and ischemia/reperfusion injury using mice with cardiac-specific expression of kinase dead (dominant negative) mutants of p38alpha (p38alphadn) or p38beta (p38betadn). Hearts were subjected to 20 min ischemia and 40 min reperfusion. Immunofluorescence staining for p38alphadn and p38betadn protein was performed on neonatal cardiomyocytes infected with adenovirus expressing flag-tagged p38alphadn and p38betadn protein. Basal contractile function was increased in both p38alphadn and p38betadn hearts compared to WT. Ischemic injury was increased in p38betadn vs. WT hearts, as indicated by lower posti-schemic recoveries of contractile function and ATP. However, despite a similar increase in contractility, ischemic injury was not increased in p38alphadn vs. WT hearts. Immunohistological analysis of cardiomyocytes with comparable levels of protein overexpression show that p38alphadn and p38betadn proteins were co-localized with sarcomeric alpha-actinin, however, p38alphadn was detected in the nucleus while p38betadn was exclusively detected in the cytosol. In summary, attenuated p38 activity led to increased myocardial contractility; specific isoforms of p38 and their sub-cellular localization may have different roles in modulating ischemic injury.
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PMID:Effect of p38 MAP kinases on contractility and ischemic injury in intact heart. 1970 73

Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by mutations in genes encoding sarcomere proteins. The mechanisms involved in the development of cardiac hypertrophy and heart failure remain poorly understood. Global proteomic profiling was used to study the cardiac proteome of mice predisposed to developing HCM. Hearts from three groups of mice (n=3 hearts per group) were studied: non-transgenic (NTG) and cardiac-specific transgenic models over-expressing either the normal (TnI(WT)) or a mutant cardiac troponin I gene (Gly203Ser; TnI(G203S)). Two-dimensional gel electrophoresis (2-DE) coupled with tandem mass spectrometry was used to identify proteins. Image analysis was performed using Progenesis SameSpots. A total of 34 proteins with at least a twofold change in the TnI(G203S) mouse model were identified. Alterations were detected in components involved in energy production, Ca(2+) handling, and cardiomyocyte structure. Expression level changes in cytoskeletal and contractile proteins were well represented in the study, including the intermediate filament protein desmin, which was further investigated in two additional physiological and pathological settings, i.e., exercise treatment, and severe heart failure in a novel double-mutant TnI-203/MHC-403 model of HCM. This study highlights the potential role of tissue proteomic profiling for mapping proteins, which may be critical in cardiac dysfunction and progression to heart failure in HCM.
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PMID:Differential protein expression profiling of myocardial tissue in a mouse model of hypertrophic cardiomyopathy. 1971

Skeletal muscle produces a myriad of mitogenic factors possessing cardiovascular regulatory effects that can be explored for cardiac repair. Given the reported findings that VEGF may modulate muscle regeneration, we investigated the therapeutic effects of chronic injections of low doses of human recombinant VEGF-A(165) (0.1-1 microg/kg) into the dystrophic hamstring muscle in a hereditary hamster model of heart failure and muscular dystrophy. In vitro, VEGF stimulated proliferation, migration, and growth factor production of cultured C2C12 skeletal myocytes. VEGF also induced production of HGF, IGF2, and VEGF by skeletal muscle. Analysis of skeletal muscle revealed an increase in myocyte nuclear [531 +/- 12 VEGF 1 microg/kg vs. 364 +/- 19 for saline (number/mm(2)) saline] and capillary [591 +/- 80 VEGF 1 microg/kg vs. 342 +/- 21 for saline (number/mm(2))] densities. Skeletal muscle analysis revealed an increase in Ki67(+) nuclei in the VEGF 1 microg/kg group compared with saline. In addition, VEGF mobilized c-kit(+), CD31(+), and CXCR4(+) progenitor cells. Mobilization of progenitor cells was consistent with higher SDF-1 concentrations found in hamstring, plasma, and heart in the VEGF group. Echocardiogram analysis demonstrated improvement in left ventricular ejection fraction (0.60 +/- 0.02 VEGF 1 microg/kg vs. 0.45 +/- 0.01 mm for saline) and an attenuation in ventricular dilation [5.59 +/- 0.12 VEGF 1 microg/kg vs. 6.03 +/- 0.09 for saline (mm)] 5 wk after initiating therapy. Hearts exhibited higher cardiomyocyte nuclear [845 +/- 22 VEGF 1 microg/kg vs. 519 +/- 40 for saline (number/mm(2))] and capillary [2,159 +/- 119 VEGF 1 microg/kg vs. 1,590 +/- 66 for saline (number/mm(2))] densities. Myocardial analysis revealed approximately 2.5 fold increase in Ki67+ cells and approximately 2.8-fold increase in c-kit(+) cells in the VEGF group, which provides evidence for cardiomyocyte regeneration and progenitor cell expansion. This study provides novel evidence of a salutary effect of VEGF in the cardiomyopathic hamster via induction of myogenic growth factor production by skeletal muscle and mobilization of progenitor cells, which resulted in attenuation of cardiomyopathy and repair of the heart.
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PMID:Intramuscular VEGF repairs the failing heart: role of host-derived growth factors and mobilization of progenitor cells. 1975 38

Phosphatase inhibitor-1 (I-1) is a distal amplifier element of beta-adrenergic signaling that functions by preventing dephosphorylation of downstream targets. I-1 is downregulated in human failing hearts, while overexpression of a constitutively active mutant form (I-1c) reverses contractile dysfunction in mouse failing hearts, suggesting that I-1c may be a candidate for gene therapy. We generated mice with conditional cardiomyocyte-restricted expression of I-1c (referred to herein as dTGI-1c mice) on an I-1-deficient background. Young adult dTGI-1c mice exhibited enhanced cardiac contractility but exaggerated contractile dysfunction and ventricular dilation upon catecholamine infusion. Telemetric ECG recordings revealed typical catecholamine-induced ventricular tachycardia and sudden death. Doxycycline feeding switched off expression of cardiomyocyte-restricted I-1c and reversed all abnormalities. Hearts from dTGI-1c mice showed hyperphosphorylation of phospholamban and the ryanodine receptor, and this was associated with an increased number of catecholamine-induced Ca2+ sparks in isolated myocytes. Aged dTGI-1c mice spontaneously developed a cardiomyopathic phenotype. These data were confirmed in a second independent transgenic mouse line, expressing a full-length I-1 mutant that could not be phosphorylated and thereby inactivated by PKC-alpha (I-1S67A). In conclusion, conditional expression of I-1c or I-1S67A enhanced steady-state phosphorylation of 2 key Ca2+-regulating sarcoplasmic reticulum enzymes. This was associated with increased contractile function in young animals but also with arrhythmias and cardiomyopathy after adrenergic stress and with aging. These data should be considered in the development of novel therapies for heart failure.
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PMID:Constitutively active phosphatase inhibitor-1 improves cardiac contractility in young mice but is deleterious after catecholaminergic stress and with aging. 2007 77

Liver kinase B1 (LKB1) is a tumor-suppressing protein that is involved in the regulation of muscle metabolism and growth by phosphorylating and activating AMP-activated protein kinase (AMPK) family members. Here we report the development of a myopathic phenotype in skeletal and cardiac muscle-specific LKB1 knockout (mLKB1-KO) mice. The myopathic phenotype becomes overtly apparent at 30-50 wk of age and is characterized by decreased body weight and a proportional reduction in fast-twitch skeletal muscle weight. The ability to ambulate is compromised with an often complete loss of hindlimb function. Skeletal muscle atrophy is associated with a 50-75% reduction in mammalian target of rapamycin pathway phosphorylation, as well as lower peroxisome proliferator-activated receptor-alpha coactivator-1 content and cAMP response element binding protein phosphorylation (43 and 40% lower in mLKB1-KO mice, respectively). Maximum in situ specific force production is not affected, but fatigue is exaggerated, and relaxation kinetics are slowed in the myopathic mice. The increased fatigue is associated with a 30-78% decrease in mitochondrial protein content, a shift away from type IIA/D toward type IIB muscle fibers, and a tendency (P=0.07) for decreased capillarity in mLKB1-KO muscles. Hearts from myopathic mLKB1-KO mice exhibit grossly dilated atria, suggesting cardiac insufficiency and heart failure, which likely contributes to the phenotype. These findings indicate that LKB1 plays a critical role in the maintenance of both skeletal and cardiac function.
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PMID:Skeletal muscle dysfunction in muscle-specific LKB1 knockout mice. 2036 Apr 28


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