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

A variety of stresses on the heart initiate a number of subcellular signaling pathways, which finally reach the nuclei of cardiac myocytes and cause myocyte hypertrophy with heart failure. However, common nuclear pathways that lead to this state are unknown. A zinc finger protein, GATA-4, is one of the transcription factors that mediate changes in gene expression during myocardial-cell hypertrophy. p300 not only acts as a transcriptional coactivator of GATA-4, but also possesses an intrinsic histone acetyltransferase activity. In primary cardiac myocytes derived from neonatal rats, we show that stimulation with phenylephrine increased an acetylated form of GATA-4 and its DNA-binding activity, as well as expression of p300. A dominant-negative mutant of p300 suppressed phenylephrine-induced nuclear acetylation, activation of GATA-4-dependent endothelin-1 promoters, and hypertrophic responses, such as increase in cell size and sarcomere organization. In sharp contrast to the activation of cardiac MEK-1, which phosphorylates GATA-4 and causes compensated hypertrophy in vivo, p300-mediated acetylation of mouse cardiac nuclear proteins, including GATA-4, results in marked eccentric dilatation and systolic dysfunction. These findings suggest that p300-mediated nuclear acetylation plays a critical role in the development of myocyte hypertrophy and represents a pathway that leads to decompensated heart failure.
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PMID:Cardiac p300 is involved in myocyte growth with decompensated heart failure. 1272 18

Cardiac hypertrophy is induced by a number of stimuli and can lead to cardiomyopathy and heart failure. Cardiomyocyte hypertrophy is characterized by increased cell size and altered gene expression. By differential-display polymerase chain reaction and Western blotting we found that the transcriptional coactivator MBF1 was upregulated during hypertrophy in cardiomyocyte cultures. Furthermore, MBF1 protein level increased in two animal models of hypertrophy, angiotensin II treatment and aortic banding. MBF1 antisense oligodeoxynuclotides blocked phenylephrine-induced hypertrophy, suggesting MBF1 plays a key role in hypertrophic growth. In contrast, overexpression of MBF1 potentiated the hormone-induced response of the atrial natriuretic peptide promoter. MBF1 overexpressed by transient transfection cooperated with the transcription factor c-Jun in activation of transcription but not with GATA4. MBF1 and c-Jun induced the activity of a transiently transfected atrial natriuretic peptide promoter, whereas neither MBF1 nor c-Jun could induce the promoter alone. Moreover, MBF1 bound to c-Jun in vitro. These data suggest that MBF1 is a transcriptional coactivator of c-Jun regulating hypertrophic gene expression. Inhibitor studies suggested that MBF1 activates the atrial natriuretic peptide promoter independently of the calcineurin and CaMK signaling pathways. Our results indicate that MBF1 participates in hormone-induced cardiomyocyte hypertrophy and activates hypertrophic gene expression as a coactivator of c-Jun.
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PMID:Multiprotein bridging factor 1 cooperates with c-Jun and is necessary for cardiac hypertrophy in vitro. 1272 99

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

Doxorubicin is an anti-tumor agent that represses cardiac-specific gene expression and induces myocardial cell apoptosis. Doxorubicin depletes cardiac p300, a transcriptional coactivator that is required for the maintenance of the differentiated phenotype of cardiac myocytes. However, the role of p300 in protection against doxorubicin-induced apoptosis is unknown. Transgenic mice overexpressing p300 in the heart and wild-type mice were subjected to doxorubicin treatment. Compared with wild-type mice, transgenic mice exhibited higher survival rate as well as more preserved left ventricular function and cardiac expression of alpha-sarcomeric actin. Doxorubicin induced myocardial cell apoptosis in wild-type mice but not in transgenic mice. Expression of p300 increased the cardiac level of bcl-2 and mdm-2, but not that of p53 or other members of the bcl-2 family. These findings demonstrate that overexpression of p300 protects cardiac myocytes from doxorubicin-induced apoptosis and reduces the extent of acute heart failure in adult mice in vivo.
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PMID:Expression of p300 protects cardiac myocytes from apoptosis in vivo. 1497 62

We identified a human mutation that causes dilated cardiomyopathy and heart failure preceded by sensorineural hearing loss (SNHL). Unlike previously described mutations causing dilated cardiomyopathy that affect structural proteins, this mutation deletes 4,846 bp of the human transcriptional coactivator gene EYA4. To elucidate the roles of eya4 in heart function, we studied zebrafish embryos injected with antisense morpholino oligonucleotides. Attenuated eya4 transcript levels produced morphologic and hemodynamic features of heart failure. To determine why previously described mutated EYA4 alleles cause SNHL without heart disease, we examined biochemical interactions of mutant Eya4 peptides. Eya4 peptides associated with SNHL, but not the shortened 193-amino acid peptide associated with dilated cardiomyopathy and SNHL, bound wild-type Eya4 and associated with Six proteins. These data define unrecognized and crucial roles for Eya4-Six-mediated transcriptional regulation in normal heart function.
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PMID:Mutation in the transcriptional coactivator EYA4 causes dilated cardiomyopathy and sensorineural hearing loss. 1573 44

Heart failure is accompanied by important defects in metabolism. The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) is a powerful regulator of mitochondrial biology and metabolism. PGC-1alpha and numerous genes regulated by PGC-1alpha are repressed in models of cardiac stress, such as that generated by transverse aortic constriction (TAC). This finding has suggested that PGC-1alpha repression may contribute to the maladaptive response of the heart to chronic hemodynamic loads. We show here that TAC in mice genetically engineered to lack PGC-1alpha leads to accelerated cardiac dysfunction, which is accompanied by signs of significant clinical heart failure. Treating cardiac cells in tissue culture with the catecholamine epinephrine leads to repression of PGC-1alpha and many of its target genes, recapitulating the findings in vivo in response to TAC. Importantly, introduction of ectopic PGC-1alpha can reverse the repression of most of these genes by epinephrine. Together, these data indicate that endogenous PGC-1alpha serves a cardioprotective function and suggest that repression of PGC-1alpha significantly contributes to the development of heart failure. Moreover, the data suggest that elevating PGC-1alpha activity may have therapeutic potential in the treatment of heart failure.
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PMID:Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-gamma coactivator 1alpha. 1677 82

Downregulation and functional deactivation of the transcriptional coactivator PGC-1alpha has been implicated in heart failure pathogenesis. We hypothesized that the estrogen-related receptor alpha (ERRalpha), which recruits PGC-1alpha to metabolic target genes in heart, exerts protective effects in the context of stressors known to cause heart failure. ERRalpha(-/-) mice subjected to left ventricular (LV) pressure overload developed signatures of heart failure including chamber dilatation and reduced LV fractional shortening. (31)P-NMR studies revealed abnormal phosphocreatine depletion in ERRalpha(-/-) hearts subjected to hemodynamic stress, indicative of a defect in ATP reserve. Mitochondrial respiration studies demonstrated reduced maximal ATP synthesis rates in ERRalpha(-/-) hearts. Cardiac ERRalpha target genes involved in energy substrate oxidation, ATP synthesis, and phosphate transfer were downregulated in ERRalpha(-/-) mice at baseline or with pressure overload. These results demonstrate that the nuclear receptor ERRalpha is required for the adaptive bioenergetic response to hemodynamic stressors known to cause heart failure.
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PMID:The nuclear receptor ERRalpha is required for the bioenergetic and functional adaptation to cardiac pressure overload. 1761 54

Diabetic cardiomyopathy, structurally characterized by cardiomyocyte hypertrophy and increased extracellular matrix (ECM) protein deposition, eventually leads to heart failure. We investigated the role of transcriptional coactivator p300 and its interaction with myocyte enhancer factor 2 (MEF2) in diabetes-induced cardiomyocyte hypertrophy. Neonatal rat cardiomyocytes were exposed to variable levels of glucose. Cardiomyocytes were analyzed with respect to their size. mRNA expression of p300, MEF2A, MEF2C, atrial natriuretic polypeptide (ANP), brain natriuretic polypeptide (BNP), angiotensinogen (ANG), cAMP-responsive element binding protein-binding protein (CBP), and protein analysis of MEF2 were done with or without p300 blockade. We investigated the hearts of STZ-induced diabetic rats and compared them with age- and sex-matched controls after 1 and 4 mo of followup with or without treatment with p300 blocker curcumin. The results were that cardiomyocytes, exposed to 25 mM glucose for 48 h, showed cellular hypertrophy and augmented mRNA expression of ANP, BNP, and ANG, molecular markers of cardiac hypertrophy. Glucose caused a duration-dependent increase of mRNA and protein expression in MEF2A and MEF2C and transcriptional coactivator p300. Curcumin, a p300 blocker, and p300 siRNA prevented these abnormalities. Similarly, ANP, BNP, and ANG mRNA expression was significantly higher in the hearts of diabetic rats compared with the controls, in association with increased p300, MEF2A, and MEF2C expression. Treatment with p300 blocker curcumin prevented diabetes-induced upregulation of these transcripts. We concluded that data from these studies demonstrate a novel glucose-induced epigenetic mechanism regulating gene expression and cardiomyocyte hypertrophy in diabetes.
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PMID:Regulation of cardiomyocyte hypertrophy in diabetes at the transcriptional level. 1841 74

The purpose of this review is to enlighten the mechanisms of skeletal muscle dysfunction in heart failure. The muscle hypothesis suggests that chronic heart failure (CHF) symptoms, dyspnoea and fatigue are due to skeletal muscle alterations. Hyperventilation due to altered ergoreflex seems to be the cause of shortness of breath. Qualitative and quantitative changes occurring in the skeletal muscle, such as muscle wastage and shift from slow to fast fibers type, are likely to be responsible for fatigue. Mechanisms leading to muscle wastage in chronic heart failure, include cytokine-triggered skeletal muscle apoptosis, but also ubiquitin/proteasome and non-ubiquitin-dependent pathways. The regulation of fibre type involves the growth hormone/insulin-like growth factor 1/calcineurin/ transcriptional coactivator PGC1 cascade. The imbalance between protein synthesis and degradation plays an important role. Protein degradation can occur through ubiquitin-dependent and non-ubiquit-independent pathways. Systems controlling ubiquitin/ proteasome activation have been described. These are triggered by tumour necrosis factor and growth hormone/ insulin-like growth factor 1. However, an important role is played by apoptosis. In humans, and experimental models of heart failure, programmed cell death has been found in skeletal muscle and interstitial cells. Apoptosis is triggered by tumour necrosis factor and in vitro experiments have shown that it can be induced by its second messenger sphingosine. Apoptosis correlates with the severity of the heart failure syndrome. It involves activation of caspases 3 and 9 and mitochondrial cytochrome c release. Sarcomeric protein oxidation and its consequent contractile impairment can form another cause of skeletal muscle dysfunction in CHF.
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PMID:Physiological basis for contractile dysfunction in heart failure. 1899 74

Despite intense investigation over the past century, the molecular mechanisms that regulate maintenance and adaptation of the heart during postnatal development are poorly understood. Myocardin is a remarkably potent transcriptional coactivator expressed exclusively in cardiac myocytes and smooth muscle cells during postnatal development. Here we show that myocardin is required for maintenance of cardiomyocyte structure and sarcomeric organization and that cell-autonomous loss of myocardin in cardiac myocytes triggers programmed cell death. Mice harboring a cardiomyocyte-restricted null mutation in the myocardin gene (Myocd) develop dilated cardiomyopathy and succumb from heart failure within a year. Remarkably, ablation of the Myocd gene in the adult heart leads to the rapid-onset of heart failure, dilated cardiomyopathy, and death within a week. Myocd gene ablation is accompanied by dissolution of sarcomeric organization, disruption of the intercalated disc, and cell-autonomous loss of cardiomyocytes via apoptosis. Expression of myocardin/serum response factor-regulated myofibrillar genes is extinguished, or profoundly attenuated, in myocardin-deficient hearts. Conversely, proapoptotic factors are induced and activated in myocardin-deficient hearts. We conclude that the transcriptional coactivator myocardin is required for maintenance of heart function and ultimately cardiomyocyte survival.
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PMID:Myocardin is required for cardiomyocyte survival and maintenance of heart function. 1985 Aug 80


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