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)

Recent research has revealed that propranolol, a beta-adrenoceptor antagonist, causes extracellular signal-regulated kinase (ERK) cascade activation, nuclear translocation of phospho-ERK and increased transcriptional activity in cultured cell lines. Given the importance of beta-adrenoceptor antagonists in the treatment of heart failure, we evaluated the capability of propranolol of promoting the ERK-dependent gene expression at the cardiomyocyte level. To this end, the gene expression of the early growth response factor 1 (Egr1), a well-recognized indicator of nuclear extracellular signal-regulated kinase 1/2 (ERK1/2) activation, was assessed by quantitative real-time RT-PCR in vivo as well as in vitro experiments. Propranolol, administered at the dose of 10 mg/kg/day in C57BL/6 mice, caused a approximately 19-fold increase of Egr1 mRNA expression in left ventricular myocardium along with a approximately 2.1-fold increase of Egr1 protein expression. Isoproterenol, a nonselective beta-adrenoceptor agonist, also increased Egr1 mRNA and protein expression but to a lesser degree. Remarkably, isoproterenol administration was associated with the development of cardiac hypertrophy, whereas propranolol-treated mice showed a completely normal cardiac morphology. The effect of propranolol on Egr1 mRNA expression was abrogated in mice lacking beta(1)- and beta(2)-adrenoceptors indicating that propranolol increases Egr1 mRNA expression in a beta-adrenoceptor-dependent manner. The role of beta-adrenoceptors was further confirmed by showing that propranolol was able to increase Egr1 mRNA and protein levels in cultured neonatal cardiomyocytes. Collectively, these results indicate that propranolol promotes Egr1 gene expression in cardiomyocytes via beta-adrenoceptors with a mechanism which is independent of its ability to antagonize the effects of catecholamines. It is also suggested that cardiomyocyte growth and Egr1 gene overexpression are not obligate processes.
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PMID:Propranolol promotes Egr1 gene expression in cardiomyocytes via beta-adrenoceptors. 1848 46

Autosomal Emery-Dreifuss muscular dystrophy and related disorders with dilated cardiomyopathy and variable skeletal muscle involvement are caused by mutations in LMNA, which encodes A-type nuclear lamins. How alterations in A-type lamins, intermediate filament proteins of the nuclear envelope expressed in most differentiated somatic cells, cause cardiomyopathy is only poorly understood. We demonstrated previously abnormal activation of the extracellular signal-regulated kinase (ERK) branch of the mitogen-activated protein kinase (MAPK) signaling cascade in hearts of Lmna H222P 'knock in' mice, a model of autosomal Emery-Dreifuss muscular dystrophy. We therefore treated Lmna(H222P/H222P) mice that develop cardiomyopathy with PD98059, an inhibitor of ERK activation. Systemic treatment of Lmna(H222P/H222P) mice with PD98059 inhibited ERK phosphorylation and blocked the activation of downstream genes in heart. It also blocked increased expression of RNAs encoding natriuretic peptide precursors and proteins involved in sarcomere organization that occurred in placebo-treated mice. Histological analysis and echocardiography demonstrated that treatment with PD98059 delayed the development of left ventricular dilatation. PD98059-treated Lmna(H222P/H222P) mice had normal cardiac ejection fractions assessed by echocardiography when placebo-treated mice had a 30% decrease. These results emphasize the role of ERK activation in the development of cardiomyopathy caused by LMNA mutations. They further provide proof of principle for ERK inhibition as a therapeutic option to prevent or delay heart failure in humans with Emery-Dreifuss muscular dystrophy and related disorders caused by mutations in LMNA.
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PMID:Inhibition of extracellular signal-regulated kinase signaling to prevent cardiomyopathy caused by mutation in the gene encoding A-type lamins. 1892 24

The purine analog xanthine oxidase (XO) inhibitors (XOIs), allopurinol and oxypurinol, have been reported to protect against heart failure secondary to myocardial infarction or rapid ventricular pacing. Because these agents might influence other aspects of purine metabolism that could influence their effect, this study examined the effect of the non-purine XOI, febuxostat, on pressure overload-induced left ventricular (LV) hypertrophy and dysfunction. Transverse aortic constriction (TAC) in mice caused LV hypertrophy and dysfunction and increased myocardial nitrotyrosine at 8 days. TAC also caused increased phosphorylated Akt (p-Akt(Ser473)), p42/44 extracellular signal-regulated kinase (p-Erk(Thr202/Tyr204)), and mammalian target of rapamycin (mTOR) (p-mTOR(Ser2488)). XO inhibition with febuxostat (5 mg/kg/d by gavage for 8 days) beginning approximately 60minutes after TAC attenuated the TAC-induced LV hypertrophy and dysfunction. Febuxostat blunted the TAC-induced increases in nitrotyrosine (indicating reduced myocardial oxidative stress), p-Erk(Thr202/Tyr204), and p-mTOR(Ser2488), with no effect on total Erk or total mTOR. Febuxostat had no effect on myocardial p-Akt(Ser473) or total Akt. The results suggest that XO inhibition with febuxostat reduced oxidative stress in the pressure overloaded LV, thereby diminishing the activation of pathways that result in pathologic hypertrophy and contractile dysfunction.
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PMID:Xanthine oxidase inhibition with febuxostat attenuates systolic overload-induced left ventricular hypertrophy and dysfunction in mice. 1899 79

Heart failure is a cause of significant morbidity and mortality in developed nations, and results from a complex interplay between genetic and environmental factors. To discover gene regulatory networks underlying heart failure, we analyzed DNA microarray data based on left ventricular free-wall myocardium from 59 failing (32 ischemic cardiomyopathy, 27 idiopathic dilated cardiomyopathy) and 33 non-failing explanted human hearts from the Cardiogenomics Consortium. In particular, we sought to investigate cardiac gene expression changes at the level of individual genes, as well as biological pathways which contain groups of functionally related genes. Utilizing a combination of computational techniques, including Comparative Marker Selection and Gene Set Enrichment Analysis, we identified a subset of downstream gene targets of the master mitochondrial transcriptional regulator, peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), whose expression is collectively decreased in failing human hearts. We also observed decreased expression of the key PGC-1alpha regulatory partner, estrogen-related receptor alpha (ERRalpha), as well as ERRalpha target genes which may participate in the downregulation of mitochondrial metabolic capacity. Gene expression of the antiapoptotic Raf-1/extracellular signal-regulated kinase (ERK) pathway was decreased in failing hearts. Alterations in PGC-1alpha and ERRalpha target gene sets were significantly correlated with an important clinical parameter of disease severity - left ventricular ejection fraction, and were predictive of failing vs. non-failing phenotypes. Overall, our results implicate PGC-1alpha and ERRalpha in the pathophysiology of human heart failure, and define dynamic target gene sets sharing known interrelated regulatory mechanisms capable of contributing to the mitochondrial dysfunction characteristic of this disease process.
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PMID:PGC-1alpha and ERRalpha target gene downregulation is a signature of the failing human heart. 1906 96

Murine transgenesis using cardioselective promoters has become increasingly common in studies of cardiac hypertrophy and heart failure, with expression mediated by pronuclear microinjection being the commonest format. Without wishing to decry their usefulness, in our view, such studies are not necessarily as unambiguous as sometimes portrayed and clarity is not always their consequence. We describe broadly the types of approach undertaken in the heart and point out some of the drawbacks. We provide three arbitrarily-chosen examples where, in spite of a number of often-independent studies, no consensus has yet been achieved. These include glycogen synthase kinase 3, the extracellular signal-regulated kinase pathway and the ryanodine receptor 2. We believe that the transgenic approach should not be viewed in an empyreal light and, depending on the questions asked, we suggest that other experimental systems provide equal (or even more) valuable outcomes.
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PMID:Are transgenic mice the 'alkahest' to understanding myocardial hypertrophy and failure? 1907 Nov 33

The clinical efficacy of exercise training in individuals with heart failure is well established, but the mechanism underlying such efficacy has remained unclear. An imbalance between cardiac hypertrophy and angiogenesis is implicated in the transition to heart failure. We investigated the effects of exercise training on cardiac pathophysiology in hypertensive rats. Dahl salt-sensitive rats fed a high-salt diet from 6 weeks of age were assigned to sedentary or exercise (swimming)-trained groups at 9 weeks. Exercise training attenuated the development of heart failure and increased survival, without affecting blood pressure, at 18 weeks. It also attenuated left ventricular concentricity without a reduction in left ventricular mass or impairment of cardiac function. Interstitial fibrosis was increased and myocardial capillary density was decreased in the heart of sedentary rats, and these effects were attenuated by exercise. Exercise potentiated increases in the phosphorylation of Akt and mammalian target of rapamycin observed in the heart of sedentary rats, whereas it inhibited the downregulation of proangiogenic gene expression apparent in these animals. The abundance of the p110alpha isoform of phosphatidylinositol 3-kinase was decreased, whereas those of the p110gamma isoform of phosphatidylinositol 3-kinase and the phosphorylation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase were increased, in the heart of sedentary rats, and all of these effects were prevented by exercise. Thus, exercise training had a beneficial effect on cardiac remodeling and attenuated heart failure in hypertensive rats, with these effects likely being attributable to the attenuation of left ventricular concentricity and restoration of coronary angiogenesis through activation of phosphatidylinositol 3-kinase(p110alpha)-Akt-mammalian target of rapamycin signaling.
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PMID:Exercise training alters left ventricular geometry and attenuates heart failure in dahl salt-sensitive hypertensive rats. 1956 40

Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) are the largest group of structurally related proteins encoded by the human genome. As signal effectors and allosteric regulators, GPCRs dynamically recruit not only specific heterotrimeric G proteins but also the cytosolic scaffold proteins, beta-arrestin 1 and 2, which were originally thought only to serve as negative regulators of GPCR signaling. Although about half of currently available therapeutics target GPCR function, usually at the ligand-binding, orthosteric site, evidence suggests that beta-arrestins may be therapeutic targets themselves. Indeed, a hitherto undiscovered action of various antipsychotics is to inhibit the ability of the dopamine D2 receptor to engage beta-arrestin 2 and activate glycogen synthase kinase 3, which may be a target for developing therapeutics for schizophrenia. Also, certain beta-antagonists (blockers) used to treat heart failure, such as carvedilol, have the added effect of promoting activation of extracellular signal-regulated kinase through beta-arrestin. It seems likely that the structure of beta-arrestins allows them to detect different types and conformational states of GPCRs and to respond in functionally distinct fashions by using separate cohorts of signaling proteins, thus generating additional possibilities for therapeutic intervention.
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PMID:Arrestin times for developing antipsychotics and beta-blockers. 1936 91

Oxidative stress plays a critical role in the progression of pathological cardiac hypertrophy and heart failure. Because crocetin represses oxidative stress in vitro and in vivo, we have suggested that crocetin would repress cardiac hypertrophy by targeting oxidative stress-dependent signalling. We tested this hypothesis using primary cultured cardiac myocytes and fibroblasts and one well-established animal model of cardiac hypertrophy. The results showed that crocetin (1-10 microM) dose-dependently blocked cardiac hypertrophy induced by angiogensin II (Ang II; 1 microM) in vitro. Our data further revealed that crocetin (50 mg/kg/day) both prevented and reversed cardiac hypertrophy induced by aortic banding (AB), as assessed by heart weight/body weight and lung weight/body weight ratios, echocardio-graphic parameters and gene expression of hypertrophic markers. The inhibitory effect of crocetin on cardiac hypertrophy is mediated by blocking the reactive oxygen species (ROS)-dependent mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase-1/2 (MEK/ERK1/2) pathway and GATA binding protein 4 (GATA-4) activation. Further investigation demonstrated that crocetin inhibited inflammation by blocking nuclear factor kappa B (NF-kappaB) signalling and attenuated fibrosis and collagen synthesis by abrogating MEK-ERK1/2 signalling. Overall, our results indicate that crocetin, which is a potentially safe and inexpensive therapy for clinical use, has protective potential in targeting cardiac hypertrophy and fibrosis by suppression of ROS-dependent signalling pathways.
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PMID:Crocetin protects against cardiac hypertrophy by blocking MEK-ERK1/2 signalling pathway. 1941 85

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

Reactive oxygen species (ROS) exert pleiotropic effects on a wide array of signaling proteins that regulate cellular growth and apoptosis. This study shows that long-term treatment with a low concentration of H2O2 leads to the activation of signaling pathways involving extracellular signal-regulated kinase, ribosomal protein S6 kinase, and protein kinase D (PKD) that increase cAMP binding response element protein (CREB) phosphorylation at Ser(133) in cardiomyocytes. Although CREB-Ser(133) phosphorylation typically mediates cAMP-dependent increases in CREB target gene expression, the H2O2-dependent increase in CREB-Ser(133) phosphorylation is accompanied by a decrease in CREB protein abundance and no change in Cre-luciferase reporter activity. Mutagenesis studies indicate that H2O2 decreases CREB protein abundance via a mechanism that does not require CREB-Ser(133) phosphorylation. Rather, the H2O2-dependent decrease in CREB protein is prevented by the proteasome inhibitor lactacystin, by inhibitors of mitogen-activated protein kinase kinase or protein kinase C activity, or by adenoviral-mediated delivery of a small interfering RNA that decreases PKD1 expression. A PKD1-dependent mechanism that links oxidative stress to decreased CREB protein abundance is predicted to contribute to the pathogenesis of heart failure by influencing cardiac growth and apoptosis responses.
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PMID:Reactive oxygen species decrease cAMP response element binding protein expression in cardiomyocytes via a protein kinase D1-dependent mechanism that does not require Ser133 phosphorylation. 1962 Feb 55


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