UMLS:C0018801 - FACTA Search

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

Glycogen synthase kinase (GSK)-3, a negative regulator of cardiac hypertrophy, is inactivated in failing hearts. To examine the histopathological and functional consequence of the persistent inhibition of GSK-3beta in the heart in vivo, we generated transgenic mice with cardiac-specific overexpression of dominant negative GSK-3beta (Tg-GSK-3beta-DN) and tetracycline-regulatable wild-type GSK-3beta. GSK-3beta-DN significantly reduced the kinase activity of endogenous GSK-3beta, inhibited phosphorylation of eukaryotic translation initiation factor 2B epsilon, and induced accumulation of beta-catenin and myeloid cell leukemia-1, confirming that GSK-3beta-DN acts as a dominant negative in vivo. Tg-GSK-3beta-DN exhibited concentric hypertrophy at baseline, accompanied by upregulation of the alpha-myosin heavy chain gene and increases in cardiac function, as evidenced by a significantly greater Emax after dobutamine infusion and percentage of contraction in isolated cardiac myocytes, indicating that inhibition of GSK-3beta induces well-compensated hypertrophy. Although transverse aortic constriction induced a similar increase in hypertrophy in both Tg-GSK-3beta-DN and nontransgenic mice, Tg-GSK-3beta-DN exhibited better left ventricular function and less fibrosis and apoptosis than nontransgenic mice. Induction of the GSK-3beta transgene in tetracycline-regulatable wild-type GSK-3beta mice induced left ventricular dysfunction and premature death, accompanied by increases in apoptosis and fibrosis. Overexpression of GSK-3beta-DN in cardiac myocytes inhibited tumor necrosis factor-alpha-induced apoptosis, and the antiapoptotic effect of GSK-3beta-DN was abrogated in the absence of myeloid cell leukemia-1. These results suggest that persistent inhibition of GSK-3beta induces compensatory hypertrophy, inhibits apoptosis and fibrosis, and increases cardiac contractility and that the antiapoptotic effect of GSK-3beta inhibition is mediated by myeloid cell leukemia-1. Thus, downregulation of GSK-3beta during heart failure could be compensatory.
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PMID:Inhibition of glycogen synthase kinase 3beta during heart failure is protective. 1804 21

Galpha(q) protein-coupled receptor (GPCR) signaling pathway, which includes diacylglycerol (DAG) and protein kinase C (PKC), plays a critical role in cardiac hypertrophy. DAG kinase (DGK) catalyzes DAG phosphorylation and controls cellular DAG levels, thus acting as a regulator of GPCR signaling. It has been reported that DGKepsilon acts specifically on DAG produced by inositol cycling. In this study, we examined whether DGKepsilon prevents cardiac hypertrophy and progression to heart failure under chronic pressure overload. We generated transgenic mice with cardiac-specific overexpression of DGKepsilon (DGKepsilon-TG) using an alpha-myosin heavy chain promoter. There were no differences in cardiac morphology and function between wild-type (WT) and DGKepsilon-TG mice at the basal condition. Either continuous phenylephrine infusion or thoracic transverse aortic constriction (TAC) was performed in WT and DGKepsilon-TG mice. Increases in heart weight after phenylephrine infusion and TAC were abolished in DGKepsilon-TG mice compared with WT mice. Cardiac dysfunction after TAC was prevented in DGKepsilon-TG mice, and the survival rate after TAC was higher in DGKepsilon-TG mice than in WT mice. Phenylephrine- and TAC-induced DAG accumulation, the translocation of PKC isoforms, and the induction of fetal genes were blocked in DGKepsilon-TG mouse hearts. The upregulation of transient receptor potential channel (TRPC)-6 expression after TAC was attenuated in DGKepsilon-TG mice. In conclusion, these results demonstrate the first evidence that DGKepsilon restores cardiac dysfunction and improves survival under chronic pressure overload by controlling cellular DAG levels and TRPC-6 expression. DGKepsilon may be a novel therapeutic target to prevent cardiac hypertrophy and progression to heart failure.
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PMID:Diacylglycerol kinase-epsilon restores cardiac dysfunction under chronic pressure overload: a new specific regulator of Galpha(q) signaling cascade. 1848 37

PYK2 is a Ca(2+)-dependent, nonreceptor protein tyrosine kinase that is involved in the induction of left ventricular hypertrophy (LVH) and its transition to heart failure. We and others have previously investigated PYK2's function in vitro using cultured neonatal and adult rat ventricular myocytes as model systems. However, the function of PYK2 in the in vivo adult heart remains unclear. Here we evaluate the effect of PYK2 inhibition following myocardial infarction (MI) using adenoviral (Adv) overexpression of the C-terminal domain of PYK2, known as CRNK. First we demonstrate that CRNK functions as a dominant-negative inhibitor of PYK2-dependent signaling, presumably by displacing PYK2 from focal adhesions and costameres. Then, male Sprague-Dawley rats (~300 g) underwent permanent left anterior descending coronary artery ligation. One wk post-MI, either Adv-GFP (n=34) or Adv-CRNK (n=28) was administered (10(10) pfu, 0.1 ml) via catheter-based, Optison-mediated gene transfer. LV structure and function were evaluated by echocardiography 1 and 3 wk after gene transfer, and LV tissue was analyzed by real-time RT-PCR and Western blotting. CRNK overexpression was readily detected by Western blotting 1 wk following gene transfer. Adv-CRNK improved overall survival (P=0.03; Logrank Test) and LV fractional shortening (23+/-2% vs. 31+/-2% for Adv-GFP vs. Adv-CRNK infected animals, respectively; P<0.05). Whereas MI hearts exhibited increased beta-, and decreased alpha-myosin heavy chain (MHC) mRNA expression characteristic of LVH, Adv-CRNK reversed the MHC isoenzyme switch (3.3+/-1.4 fold increase in alpha MHC; 0.4+/-0.1 fold decrease in beta MHC; P<0.05 for both). In summary, CRNK gene transfer improves survival, increases LV function, and alters MHC gene expression suggesting an attenuation of LV remodeling post-MI.
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PMID:CRNK gene transfer improves function and reverses the myosin heavy chain isoenzyme switch during post-myocardial infarction left ventricular remodeling. 1849 52

MicroRNAs (miRNAs) are small, noncoding ~22-nucleotide regulatory RNAs that are key regulators of gene expression programs. Their role in the context of the cardiovascular system has only recently begun to be explored; however, changes in the expression of miRNAs have been associated with cardiac development and with several pathophysiological states including myocardial hypertrophy and heart failure. We demonstrate that miRNA expression patterns are distinct in two types of heart failure: idiopathic dilated cardiomyopathy and ischemic cardiomyopathy. To pursue the observation that changes in expression levels of individual miRNAs are functionally relevant, microRNA mimics and inhibitors to miR-92, miR-100 and miR-133b were expressed in primary cultures of neonatal rat cardiac myocytes. These studies demonstrated that over-expression of miR-100 is involved in the beta-adrenergic receptor-mediated repression of "adult" cardiac genes (i.e., alpha-myosin heavy chain, SERCA2a), and that over-expression of miR-133b prevents changes in gene expression patterns mediated by beta-adrenergic receptor stimulation. In conclusion, some miRNA expression patterns appear to be unique to the etiology of cardiomyopathy and changes in the expression level of miRs 100 and 133b contribute to regulation of the fetal gene program. It is likely that this miR-directed reprogramming of key remodeling genes is involved in the establishment and progression of common human cardiomyopathies.
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PMID:miRNA expression in the failing human heart: functional correlates. 1861 9

The prolonged production of reactive oxygen species due to ischemia-reperfusion (I/R) is a potential cause of the pathological remodeling that frequently precedes heart failure. We tested the ability of a potent dithiol antioxidant, bucillamine, to protect against the long-term consequences of I/R injury in a murine model of myocardial infarction. After transiently occluding the left anterior descending coronary artery for 30 min, saline or bucillamine (10 microg/g body wt) was injected intravenously as a bolus within the first 5 min of reperfusion. The antioxidant treatment continued with daily subcutaneous injections for 4 wk. There were no differences in infarct sizes between bucillamine- and saline-treated animals. After 4 wk of reperfusion, cardiac hypertrophy was decreased by bucillamine treatment (ventricular weight-to-body weight ratios: I/R + saline, 4.5 +/- 0.2 mg/g vs. I/R + bucillamine, 4.2 +/- 0.1 mg/g; means +/- SE; P < 0.05). Additionally, the hearts of bucillamine-treated mice had improved contractile function (echocardiographic measurement of fractional shortening) relative to saline controls: I/R + saline, 32 +/- 3%, versus I/R + bucillamine, 41 +/- 4% (P < 0.05). Finally, I/R-induced injury in the saline-treated mice was accompanied by a fetal pattern of gene expression determined by ribonuclease protection assay that was consistent with pathological cardiac hypertrophy and remodeling [increased atrial natriuretic peptide, beta-myosin heavy chain (MHC), skeletal alpha-actin; decreased sarco(endo)plasmic reticulum Ca2+ ATPase 2a, and alpha-MHC-to-beta-MHC ratio]. These changes in gene expression were significantly attenuated by bucillamine. Therefore, treatment with a dithiol antioxidant for 4 wk after I/R preserved ventricular function and prevented the abnormal pattern of gene expression associated with pathological cardiac remodeling.
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PMID:Prolonged administration of a dithiol antioxidant protects against ventricular remodeling due to ischemia-reperfusion in mice. 1868 93

The ischemic death of cardiomyocytes is associated in heart disease and heart failure. However, the molecular mechanism underlying ischemic cell death is not well defined. To examine the function of apoptosis repressor with a caspase recruitment domain (ARC) in the ischemic/hypoxic damage of cardiomyocytes, we generated cardio-specific ARC transgenic mice using a mouse alpha-myosin heavy chain promoter. Compared with the control, the hearts of ARC transgenic mice showed a 3-fold overexpression of ARC. Langendoff preparation showed that the hearts isolated from ARC transgenic mice exhibited improved recovery of contractile performance during reperfusion. The cardiomyocytes cultured from neonatal ARC transgenic mice were significantly resistant to hypoxic cell death. Furthermore, the ARC C-terminal calcium-binding domain was as potent to protect cardiomyocytes from hypoxic cell death as ARC. Genome-wide RNA expression profiling uncovered a list of genes whose expression was changed (>2-fold) in ARC transgenic mice. Among them, expressional regulation of developmentally regulated RNA-binding protein 1 (Drbp1) or the dimethylglycine dehydrogenase precursor (pMe(2)GlyDH) affected hypoxic death of cardiomyocytes. These results suggest that ARC may protect cardiomyocytes from hypoxic cell death by regulating its downstream, Drbp1 and pMe(2)GlyDH, shedding new insights into the protection of heart from hypoxic damages.
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PMID:Protection of cardiomyocytes from ischemic/hypoxic cell death via Drbp1 and pMe2GlyDH in cardio-specific ARC transgenic mice. 1878 77

Mitochondrial dysfunction is implicated in the pathogenesis of diabetic cardiomyopathy, a common complication of diabetes. Adenosine nucleotide translocase (ANT) translocates ADP/ATP across the inner mitochondrial membrane. Our study aimed to test the hypothesis that overexpression of ANT1 in cardiomyocytes has cardioprotective effects in diabetic cardiomyopathy induced by streptozotocin (STZ). Mice specifically overexpressing murine ANT1 in the heart were generated using alpha-myosin heavy chain promoter. Expression of ANT1 mRNA and protein in hearts was characterized by real-time polymerase chain reaction and Western blot analysis. Five- to 6-month-old male transgenic mice and their age-matched wild-type littermates were subjected to type 1 diabetes induced by STZ. Six weeks later, haemodynamic measurement was performed to assess cardiac function. Ventricular mRNA expression of atrial natriuretic peptide, a molecular marker of heart failure, was characterized by RNase-protection assay. Both ANT1 mRNA and ANT1 protein were specifically overexpressed in the heart of transgenic mice. Heart weight was decreased and cardiac function was dramatically impaired in wild-type mice 6 weeks after induction of diabetes, but ANT1 overexpression prevented these significant changes. The mRNA expression level of atrial natriuretic peptide confirmed the haemodynamic findings, being upregulated in wild-type mice receiving STZ, but showing no statistical differences in ANT1 transgenic mice. Cardiomyocyte-restricted overexpression of ANT1 prevents the development of diabetic cardiomyopathy; therefore, accelerated ADP/ATP exchange could be a new promising target to treat diabetic cardiomyopathy.
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PMID:Myocardial overexpression of adenine nucleotide translocase 1 ameliorates diabetic cardiomyopathy in mice. 1894 56

Embryonic Stem (ES) cells-derived cardiomyocytes can possibly be applied for cell therapy of diseases such as heart failure. Biodegradable scaffolds will significantly improve the expansion of sufficient functional ES cell-derived cardiomyocytes and may also increase the survival rate of cardiomyocytes after their transplantation. In the present study, we cultivated cardiomyocytes isolated from a transgenic a-myosin heavy chain (alpha-MHC) ES cell lineage expressing both puromycin resistance and enhanced green fluorescent protein (EGFP) under the control of the alpha-MHC promoter in macroporous gelatine microspheres using small-scale bioreactors and proved that cardiomyocytes function after their cultivation in micropsperes. The average number of cultivated cells per microsphere was optimised once the most suitable agitation conditions and the optimal timeframe of cultivation were identified. Our study shows that 72% of CultiSpher-S beads were colonised by cardiomyocytes under optimal conditions. Scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) showed that colonization of the beads was not limited to the surface, but that cells also invaded the inner surfaces of the microspheres. Electrophysiological experiments demonstrated that the action potentials (APs) of alpha-MHC(+) cardiomyocytes entrapped in microspheres were identical to action potentials of control cells. This attractive approach for cultivation and expansion of functional cardiomyocytes in biodegradable macroporous may offer a perspective for higher transplantation efficiencies of ES cell-derived cardiomyocytes.
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PMID:Entrapment of embryonic stem cells-derived cardiomyocytes in macroporous biodegradable microspheres: preparation and characterization. 1908 48

Though the administration of taurine is clinically efficacious against heart failure, the mechanism underlying its cardioprotection remains to be established. To provide information on the mechanism, we examined the effects of taurine on doxorubicin (DOX)-induced cardiotoxicity, with an emphasis on ROS generation and cardiac gene inhibition. Oral administration of taurine (3% w/v in tap water) dramatically reduced the mortality rate in both the acute or sub-acute toxic models of DOX toxicity. It was shown that taurine prevented DOX-induced oxidative stress as determined from cardiac glutathione content. Interestingly, Northern blot analysis revealed that DOX altered cardiac gene expression, including that of alpha-myosin heavy chain, ventricular myosin light chain-2 isoform and brain natriuretic peptide, an effect partially ameliorated by taurine treatment. In conclusion, taurine suppresses ROS generation and regulates gene expression in the DOX treated heart.
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PMID:Beneficial effect of taurine treatment against doxorubicin-induced cardiotoxicity in mice. 1923 37

1. Transition from compensated left ventricular (LV) hypertrophy to decompensated heart failure was characterized using a pressure-overload induced model to elucidate the temporal relationship between cardiomyocyte apoptosis and survival signalling in this transition. 2. Mice were subjected to transverse aortic constriction (TAC) or sham operation for 1-16 weeks and were studied by echocardiography, catheterization and histology. Relevant gene expression and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, Akt and glycogen synthase kinase (GSK)-3beta were determined. 3. Transverse aortic constriction resulted in myocyte hypertrophy and fibrosis from Week 4 and a progressive increase in left ventricular (LV) dimensions and wall thicknesses with maintained contractile function by Week 12. However, a sharp decline in contractile function and elevated LV end-diastolic pressure from 12 to 16 weeks were observed after TAC, indicating functional decompensation. 4. Following TAC, mRNA levels of atrial natriuretic peptide, B-type natriuretic peptide, beta-myosin heavy chain (MHC) and transforming growth factor-beta1 were increased time dependently, whereas mRNA expression of alpha-MHC, sarcoplasmic/endoplasmic reticulum calcium ATPase 2a and Bcl-2 were decreased. The ratio of Bcl-2/Bax was decreased and this was consistent with progressively increased myocyte apoptosis demonstrated by terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling staining. Phosphorylation of ERK1/2 was increased by Week 4, but decreased thereafter. Levels of phosphorylated Akt declined from Week 8, whereas GSK3beta phosphorylation increased from 1 to 8 weeks, then decreased from Week 12 after TAC. 5. In conclusion, TAC resulted in early concentric and late eccentric hypertrophy with eventual development of LV dysfunction. This transition was temporally associated with a progressive increase in cell size, fibrosis and myocyte apoptosis. Downregulation of ERK1/2, Akt and GSK3beta and enhanced cardiomyocyte apoptosis are implicated as important mechanisms in the transition from compensated hypertrophy to heart failure.
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PMID:Downregulation of survival signalling pathways and increased apoptosis in the transition of pressure overload-induced cardiac hypertrophy to heart failure. 1965 Jul 91

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