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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiomyocyte apoptosis and cardiac fibroblast proliferation are characteristic features of failing myocardium. Here we investigated the effect of superoxide on the cell fate of cardiomyocytes and cardiac fibroblasts. Cultured rat cardiomyocytes or cardiac fibroblasts were treated with superoxide. In response to superoxide stimulation cardiomyocytes underwent apoptosis as revealed by the increase in histone associated DNA fragmentation and positive to in situ nick end-labeling. In contrast, cardiac fibroblasts were stimulated to proliferate as demonstrated by the increase in DNA synthesis detected by [3H]thymidine incorporation and in cell number. Additionally, Northern blot analysis showed that transforming growth factor-beta1, a key factor responsible for myocardial fibrosis, was upregulated in cardiac fibroblasts in response to superoxide stimulation. These data suggest that superoxide can induce such divergent effects as apoptosis in cardiomyocytes and cell growth in cardiac fibroblasts, indicating that it may be a potential factor involved in the pathogenesis of heart failure.
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PMID:Superoxide induces apoptosis in cardiomyocytes, but proliferation and expression of transforming growth factor-beta1 in cardiac fibroblasts. 1021 77

The potential of Ca(2+) channel antagonists, particularly nifedipine, to cause apoptotic cell death has been controversial and is of considerable importance for cardiomyocytes as loss of these cells is an important component of the pathophysiology leading to heart failure. To examine the hypothesis that nifedipine induces cell death and modulates calcium-induced apoptosis, cardiomyocytes in culture from embryonic chick hearts, that readily manifest apoptosis, were studied. Apoptosis was evaluated by fluorescent activated cell sorting (FACS) analysis and by quantitative analysis of DNA fragmentation by an enzyme-linked immunosorbent assay (ELISA) specific for histone-associated DNA fragments of mono- and oligonucleosome size. Cell death was evaluated by using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay. Cardiomyocytes were treated with various concentrations of nifedipine over a concentration range relevant to serum concentrations in man. Nifedipine, 1 to 100 microM, did not produce cell death in cardiomyocytes. There was no evidence of apoptosis on FACS analysis of cardiomyocytes stained with fluoresceine diacetate or propidum iodide (PI). Neither was there any evidence of apoptotic nuclei on PI staining of permeabilized cardiomyocytes treated with nifedipine. In contrast, DNA fragmentation consistent with apoptosis was induced in a significant (P<0.05) concentration-dependent manner, by increases in extracellular Ca(2+) concentration ([Ca(2+)](o)). Importantly, nifedipine reduced DNA fragmentation produced by increased [Ca(2+)](o). Furthermore, nifedipine blocked calcium-induced cell death as high [Ca(2+)](o) significantly (P<0. 05) reduced cell viability. These data indicate that nifedipine does not induce apoptosis in cardiomyocytes rather apoptosis in cardiomyocytes is under regulatory control by Ca(2+) and nifedipine can antagonize Ca(2+)-mediated apoptotic cell death.
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PMID:Nifedipine does not induce but rather prevents apoptosis in cardiomyocytes. 1067 28

Cardiac myocyte apoptosis has been demonstrated in end-stage failing human hearts. The therapeutic utility of blocking apoptosis in congestive heart failure (CHF) has not been elucidated. This study investigated the role of caspase activation in cardiac contractility and sarcomere organization in the development of CHF. In a rabbit model of heart failure obtained by rapid ventricular pacing, we demonstrate, using in vivo transcoronary adenovirus-mediated gene delivery of the potent caspase inhibitor p35, that caspase activation is associated with a reduction in contractile force of failing myocytes by destroying sarcomeric structure. In this animal model gene transfer of p35 prevented the rise in caspase 3 activity and DNA-histone formation. Genetically manipulated hearts expressing p35 had a significant improvement in left ventricular pressure rise (+dp/dt), decreased end-diastolic chamber pressure (LVEDP), and the development of heart failure was delayed. To better understand this benefit, we examined the effects of caspase 3 on cardiomyocyte dysfunction in vitro. Microinjection of activated caspase 3 into the cytoplasm of intact myocytes induced sarcomeric disorganization and reduced contractility of the cells. These results demonstrate a direct impact of caspases on cardiac function and may lead to novel therapeutic strategies via antiapoptotic regimens.
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PMID:Blocking caspase-activated apoptosis improves contractility in failing myocardium. 1174 96

The heart responds to stress signals by hypertrophic growth, which is accompanied by activation of the MEF2 transcription factor and reprogramming of cardiac gene expression. We show here that class II histone deacetylases (HDACs), which repress MEF2 activity, are substrates for a stress-responsive kinase specific for conserved serines that regulate MEF2-HDAC interactions. Signal-resistant HDAC mutants lacking these phosphorylation sites are refractory to hypertrophic signaling and inhibit cardiomyocyte hypertrophy. Conversely, mutant mice lacking the class II HDAC, HDAC9, are sensitized to hypertrophic signals and exhibit stress-dependent cardiomegaly. Thus, class II HDACs act as signal-responsive suppressors of the transcriptional program governing cardiac hypertrophy and heart failure.
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PMID:Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. 1220 37

Yin Yang 1 (YY1) is a transcription factor that can repress or activate transcription of the genes with which it interacts. In this report we show that YY1 is a negative regulator of the alpha-myosin heavy chain (alphaMyHC) gene, which, with betaMyHC are the molecular motors of the heart. AlphaMyHC mRNA and protein levels are down-regulated in hypertrophy and heart failure, and this is thought to be detrimental for cardiac contractility. We show that YY1 specifically interacts with the alphaMyHC promoter and that overexpression of YY1 in cardiac cells represses the activity of the alphaMyHC promoter. We also show that the 170-200-amino acid region of YY1, important for its interaction with histone acetyl transferases and histone deacetylases, is important for its repressive activity and that YY1 deleted in this region is an activator of the alphaMyHC promoter. Moreover, we show that YY1 levels and DNA binding activity are increased in failing human left ventricles and in a mouse model of hypertrophic cardiomyopathy, where alphaMyHC levels are decreased. These results suggest that YY1 is a negative regulator of alphaMyHC gene expression.
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PMID:Yin Yang 1 is increased in human heart failure and represses the activity of the human alpha-myosin heavy chain promoter. 1275 14

Postnatal cardiac myocytes respond to stress signals by hypertrophic growth and activation of a fetal gene program. Recently, we showed that class II histone deacetylases (HDACs) suppress cardiac hypertrophy, and mice lacking the class II HDAC, HDAC9, are sensitized to hypertrophic signals. To further define the roles of HDACs in cardiac hypertrophy, we analyzed the effects of HDAC inhibitors on the responsiveness of primary cardiomyocytes to hypertrophic agonists. Paradoxically, HDAC inhibitors imposed a dose-dependent blockade to hypertrophy and fetal gene activation. We conclude that distinct HDACs play positive or negative roles in the control of cardiomyocyte hypertrophy. HDAC inhibitors are currently being tested in clinical trials as anti-cancer agents. Our results suggest that these inhibitors may also hold promising clinical value as therapeutics for cardiac hypertrophy and heart failure.
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PMID:Dose-dependent blockade to cardiomyocyte hypertrophy by histone deacetylase inhibitors. 1276 Dec 26

A cellular target of adenovirus E1A oncoprotein, p300 is a transcriptional coactivator required for the maintenance of differentiated phenotypes in cardiac myocytes. The full transcriptional activities of hypertrophy-responsive transcription factors such as GATA-4 and MEF2 require interaction with p300. A p300 protein also possesses intrinsic histone acetyl transferase activity, which promotes a transcriptionally active chromatin configuration. Here, we review the biological functions of p300 in cardiac myocytes. Although p300 is biologically active in many cell types, this protein appears to play a crucial role in the differentiation, growth and apoptosis of cardiac myocytes. Understanding precise mechanisms of its biological functions will shed light on molecular pathways for heart failure.
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PMID:Biological role of p300 in cardiac myocytes. 1287 Jun 62

In the future treatment of haemophilia B, a real breakthrough may be a strategy that uses site-specific genomic integration of a gene therapy vector to produce therapeutic levels of human clotting factor IX (FIX). A clinically relevant expression of plasma levels of FIX was noted for over 12 months. The strategy will be applicable for a broad range of therapeutic genes and tissues. Following the concept that angiogenic growth factors could stimulate revascularisation, a highly interesting novel approach to the 'bio-bypass' has been presented that appears to have some unexpected advantages. It was demonstrated that specifically designed transcription factors can regulate gene expression in vivo. Another important finding was that myocardial stress signals all appear to converge to a common downstream target, the class II histone deacetylases. In mice, hypertrophic stimuli proved to lead to the activation of a novel and so far unique cardiac HDAC kinase that phosphorylates the signal-responsive sites in class II HDACs. A major implication is that the cardiomyocytic HDAC kinase could well be a novel therapeutic target for the treatment of hypertrophy and heart failure. And finally, Catherine Verfaillie and her group published a landmark paper demonstrating that pluripotent stem cells that have the potency to differentiate into most, if not all, somatic tissues can also be isolated from adult bone marrow.
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PMID:Molecular biology and genetics in cardiovascular research: highlights of 2002. 1291 47

Diverse etiologic factors trigger a cardiac remodeling process in which the heart becomes abnormally enlarged with a consequent decline in cardiac function and eventual heart failure. Heart failure is traditionally treated with drugs that antagonize early signaling events at or near the cell membrane. Although such approaches have short-term efficacy, the five-year mortality rate for patients with late-stage heart failure continues to exceed 50%. Because of the redundant nature of the signaling networks that drive cardiac pathogenesis, targeting the common downstream elements of the cascades would be a more effective therapeutic strategy. Recent studies point to the importance of enzymes that control histone acetylation as stress-responsive regulators of gene expression in the heart. Given their role as nuclear integrators that couple divergent upstream signals to the gene program for cardiac remodeling, we propose that these chromatin-modifying factors represent auspicious targets for the pharmacological manipulation of cardiac disease.
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PMID:Cardiac histone acetylation--therapeutic opportunities abound. 1504 Nov 75

Diverse aetiological factors, including myocardial infarction, hypertension and contractile abnormalities, trigger a cardiac remodelling process in which the heart becomes abnormally enlarged with a consequent decline in cardiac function and eventual heart failure. Pathological cardiac hypertrophy is accompanied by the activation of a fetal cardiac gene programme, which contributes to maladaptive changes in contractility and calcium handling. Traditional treatment for heart failure involves administration of drugs that antagonize early signalling events at or near the cell membrane (e.g. cell surface receptor or ion channels). Given the complexity and redundant nature of the signalling networks that drive cardiac pathogenesis, a potentially more efficacious therapeutic strategy for disrupting the disease process would be to target common downstream elements in pathological signalling cascades. We have shown that class II histone deacetylases (HDACs) suppress cardiac hypertrophy, and mice lacking class II HDACs are sensitized to hypertrophic signals. Paradoxically, HDAC inhibitors also block cardiac hypertrophy and fetal gene activation. Based on these findings, we propose that distinct HDACs play positive or negative roles in the control of cardiac growth by regulating opposing sets of target genes via their interactions with different sets of transcription factors.
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PMID:Dual roles of histone deacetylases in the control of cardiac growth. 1517 Dec 51


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