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)

Cardiac dysfunction in animals with congestive heart failure due to myocardial infarction (MI) is known to be associated with a wide variety of defects in receptor and post-receptor mechanisms. Since the heart function have been shown to be improved by treatment with different angiotensin converting enzyme (ACE) inhibitors, we examined the effects of imidapril, an ACE inhibitor, on changes in post-receptor mechanisms involving adenylyl cyclase (AC) and G proteins in the failing heart. Heart failure in rats was induced by occluding the coronary artery and 3 weeks later the animals were treated daily with 1 mg/kg (orally) imidapril for 5 weeks. The animals were assessed for their left ventricular function and crude membranes were isolated from the viable left ventricle and examined for AC activities as well as G-protein activities and expression. Animals with heart failure exhibited depressions in ventricular function and AC activities in the absence or presence of forskolin, NaF and Gpp(NH)p. The AC activity in the presence of pertussis toxin was increased whereas that in the presence of cholera toxin was decreased in the failing heart. Protein contents and mRNA levels for G(i)-proteins were increased whereas those for G(s)-proteins were unaltered in the infarcted heart. All these changes due to MI were prevented by imidapril treatment. The results indicate that the depressed cardiac function in the failing heart may partly be due to the direct effects of changes in AC and G(i) proteins.
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PMID:Attenuation of changes in G(i)-proteins and adenylyl cyclase in heart failure by an ACE inhibitor, imidapril. 1459 52

Beta-blockers have beneficial effects in heart failure, although the underlying mechanism is unknown. Beta2-adrenoceptors, however, are proportionally higher in the failing human heart. This study shows several clinically used beta-blockers are agonists at the human beta2-adrenoceptor. Although these agonist effects were small at the cAMP level, they were substantial at the level of cAMP response element (CRE)-mediated gene transcription. Some of the effects of "beta-blockers" seen in heart failure may be related to the beta2-agonist actions of these compounds. CRE-gene transcription responses to beta2-agonists, forskolin, and cAMP-analogs were sensitive to p42/44-mitogen-activated protein (MAP) kinase pathway inhibitors. p42/44-MAP kinase activation was also shown directly by western blotting and enzyme-linked immunosorbent assay techniques. N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H89; a protein kinase A inhibitor) stimulated cAMP accumulation and CRE gene transcription via the beta2-adrenoceptor at concentrations at which protein kinase A was inhibited, providing evidence for an alternative pathway. Propranolol, however, produced paradoxical effects; it reduced basal cAMP accumulation (via beta2-mediated inverse agonism) but stimulated beta2-mediated CRE gene transcription. This cannot be explained by a sequential pathway from Gs-adenylyl cyclase-cAMP to CRE binding protein phosphorylation. Both responses to propranolol were insensitive to pertussis toxin, thus excluding Gi-protein involvement. Propranolol CRE gene transcription responses were attenuated by p42/44-MAP kinase inhibitors and propranolol was also found to directly stimulate the p42/44-MAP kinase pathway. Studies of inositol phosphate accumulation and of protein kinase C or Rho kinase inhibitors on CRE-gene transcription provided no evidence for Gq/11 or G12/13 involvement. These data suggest that propranolol can simultaneously act as an inverse agonist through a Gs-coupled mechanism while stimulating the p42/44-MAP kinase pathway through an alternative G-protein-independent mechanism.
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PMID:Agonist and inverse agonist actions of beta-blockers at the human beta 2-adrenoceptor provide evidence for agonist-directed signaling. 1464 66

Heart failure is accompanied by stereotypic alterations in cardiac gene expression. These changes are most likely secondary in the pathogenesis and can be viewed as protective, e.g. as energy-saving mechanisms, but at the same time, they aggravate contractile dysfunction and the deficit of failing cardiac myocytes to respond to altered hemodynamic needs. One of the best-studied, paradigmatic examples of this dichotomy is heterologous desensitization of the cardiac adenylyl cyclase (AC) signaling pathway. It protects against detrimental consequences of the excessive adrenergic drive, but it also blunts the most powerful inotropic support of the heart. Desensitization is associated with downregulation of beta-adrenergic receptors, increased beta-adrenoceptor kinases and increased inhibitory G protein alpha-subunits, G(alphai). Whereas a causative role of the former is generally accepted, the role of the increase in G(alphai) has remained controversial for many years. The present article summarizes early and novel findings that, in the view of the authors, provide solid evidence for G(alphai) to play an important role in the adaptation of cardiac AC to various pathophysiological conditions.
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PMID:Inhibitory G-proteins and their role in desensitization of the adenylyl cyclase pathway in heart failure. 1465 93

Unlike most other experimental models of congestive heart failure, the volume overload model induced by aortocaval shunt (AVS) in rats was found to exhibit enhanced beta-adrenoceptor (beta-AR) signaling. To study whether the adenylyl cyclase (AC)-G protein system is involved in such a change, we examined cardiac AC activity and protein content as well as G(s)alpha and G(i)alpha activities, protein contents, and mRNA levels in both left (LV) and right (RV) ventricles at the failing stage (16 wk after surgery). Basal and forskolin-stimulated AC activities were significantly increased in both LV and RV from the failing hearts; this change was associated with an upregulation of type V/VI AC protein. In contrast to 5'-guanylyl imidodiphosphate and NaF, the stimulatory effect of isoproterenol on AC was increased in the failing heart. Although G(s)alpha and G(i)alpha protein contents in the failing hearts were not altered, the mRNA level for G(s)alpha was decreased by 20% and that for G(i)alpha was increased by 20%. In addition, the activity of G(s)alpha, but not G(i)alpha, as assessed by toxin-catalyzed ADP ribosylation, was significantly decreased in the failing heart. Losartan and imidapril treatments improved cardiac function and attenuated alterations in mRNA levels for G(s)alpha and G(i)alpha proteins, as well as G(s)alpha activity, without affecting changes in AC protein content or activities in heart failure due to volume overload. These data suggest that increased AC activity may contribute to the enhanced beta-AR signaling in the AVS model of heart failure, whereas alterations in gene expression for G proteins may be of an adaptive nature at this stage of heart failure.
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PMID:Alterations of adenylyl cyclase and G proteins in aortocaval shunt-induced heart failure. 1496 38

In the heart, stimulation of beta-adrenergic receptors (betaAR) serves as the most powerful means to increase cardiac contractility and relaxation in response to stress or a "fight-or-flight" situation. However, sustained beta-adrenergic stimulation promotes pathological cardiac remodeling such as myocyte hypertrophy, apoptosis and necrosis, thus contributing to the pathogenesis of chronic heart failure. Over the past decade, compelling evidence has demonstrated that coexisting cardiac betaAR subtypes, mainly beta(1)AR and beta (2)AR, activate markedly different signaling cascades. As a result, acute beta(1)AR stimulation activates the G(s) -adenylyl cyclase-cAMP-PKA signaling that can broadcast throughout the cell, whereas beta(2)AR-evoked cAMP signaling is spatially and functionally compartmentalized, due to concurrent G(i) activation. Chronic stimulation of beta(1)AR and beta(2)AR elicits opposing effects on the fate of cardiomyocytes: beta(1)AR induces hypertrophy and apoptosis; but beta(2)AR promotes cell survival. The cardiac protective effect of beta(2)AR is mediated by a signaling pathway sequentially involving G(i), G(betagamma), PI3K and Akt. Unexpectedly, beta(1)AR-induced myocyte hypertrophy and apoptosis are independent of the classic cAMP/PKA pathway, but require activation of Ca(2+)/calmodulin-dependent kinase II (CaMK II). The outcomes of cardiac-specific transgenic overexpression of either beta AR subtype in mice have reinforced the fundamentally different functional roles of these betaAR subtypes in governing cardiac remodeling and performance. These new insights regarding betaAR subtype stimulation not only provide clues as to cellular and molecular mechanisms underlying the beneficial effects of beta AR blockers in patients with chronic heart failure, but also delineate rationale for combining selective beta(1)AR blockade with moderate beta(2)AR activation as a potential novel therapy for the treatment of chronic heart failure.
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PMID:Distinct beta-adrenergic receptor subtype signaling in the heart and their pathophysiological relevance. 1498 22

The autonomic nervous system (ANS), a complex and self-organized entity, plays a crucial role in cardiovascular regulation. In this review, the authors describe some concepts of anatomo-physiology and cellular/molecular biology of the ANS and of its two major components, the parasympathetic and sympathetic system, both in the normal individual and in the patient with heart failure. Adrenergic and cholinergic neurotransmission, neurotransmitters, adrenergic and cholinergic receptors and intracellular signal transduction are discussed. Some aspects of sympathetic-parasympathetic interaction at the cellular level are described as well as the opposite role of two cyclic nucleotides, cyclic adenosine and guanosine monophosphate. Major emphasis is placed on the beta-adrenergic system, the combination of the beta receptor, G protein complex and adenylyl cyclase. The activation of neurohumoral compensatory mechanisms in heart failure is discussed as well as the increasingly recognized importance of sympathetic overactivation and parasympathetic tonus reducting in this setting. Cellular mechanisms of adrenergic stimulation in heart failure and its consequences are presented, with special focus on down-regulation of beta-1 adrenergic receptors; the authors analyze the steps of phosphorlation and oncoupling, sequestration, internalization and lysosomal degradation, the main result of which is reduced response to catecholamines.
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PMID:[Autonomic nervous system in heart failure]. 1522 50

The traditional notion that catecholamine actions are mediated by the predominant beta(1)-adrenergic receptor (beta(1)-AR) subtype linked to the activation of adenylyl cyclase and the accumulation of cyclic adenosine 3',5'-monophosphate (cAMP) in cardiomyocytes has been challenged by recent studies showing that cardiomyocytes co-express pharmacologically distinct beta(2)-AR subtypes that activate a more broad range of downstream effectors. While beta(1)- and beta(2)-ARs exert largely functionally equivalent cellular actions in heterologous expression systems, signaling by endogenous beta-AR subtypes in highly differentiated cells such as cardiomyocytes can be strikingly different. There is growing evidence that certain features of the signaling phenotypes for beta-AR subtypes in cardiomyocytes are inconsistent with traditional models that attribute signaling specificity to high-affinity protein-protein interactions between receptors, G-proteins, and effectors freely mobile on surface membranes. This chapter summarizes recent studies that focus on membrane microdomains (such as caveolae or lipid rafts) as sites that differentially localizing individual beta-AR subtypes as well as the downstream signaling machinery that generates, propagates, and downregulates the cAMP-protein kinase A signaling pathway. To the extent that this mechanism calibrates beta-AR responses in cardiomyocytes, it would be expected to be pertinent to the pathogenesis of heart failure, where chronic/persistent beta-AR signaling contributes to ventricular remodeling and impacts on long-term survival.
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PMID:beta(2)-Adrenergic receptor signaling complexes in cardiomyocyte caveolae/lipid rafts. 1527 11

Earlier studies have revealed an improvement of cardiac function in animals with congestive heart failure (CHF) due to myocardial infarction (MI) by treatment with angiotensin converting enzyme (ACE) inhibitors. Since heart failure is also associated with attenuated responses to catecholamines, we examined the effects of imidapril, an ACE inhibitor, on the beta-adrenoceptor (beta-AR) signal transduction in the failing heart. Heart failure in rats was induced by occluding the coronary artery, and 3 weeks later the animals were treated with g/(kg x day) (orally) imidapril for 4 weeks. The animals were assessed for their left ventricular function and inotropic responses to isoproterenol. Cardiomyocytes and crude membranes were isolated from the non-ischemic viable left ventricle and examined for the intracellular concentration of Ca2+ [Ca2+]i and beta-ARs as well as adenylyl cyclase (AC) activity, respectively. Animals with heart failure exhibited depressions in ventricular function and positive inotropic response to isoproterenol as well as isoproterenol-induced increase in [Ca2+]i in cardiomyocytes; these changes were attenuated by imidapril treatment. Both beta1-AR receptor density and isoproterenol-stimulated AC activity were decreased in the failing heart and these alterations were prevented by imidapril treatment. Alterations in cardiac function, positive inotropic effect of isoproterenol, beta1-AR density and isoproterenol-stimulated AC activity in the failing heart were also attenuated by treatment with another ACE inhibitor, enalapril and an angiotensin II receptor antagonist, losartan. The results indicate that imidapril not only attenuates cardiac dysfunction but also prevents changes in beta-AR signal transduction in CHF due to MI. These beneficial effects are similar to those of enalapril or losartan and thus appear to be due to blockade of the renin-angiotensin system.
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PMID:Changes in beta-adrenoceptors in heart failure due to myocardial infarction are attenuated by blockade of renin-angiotensin system. 1552 63

ATP is released as a cotransmitter together with catecholamines from sympathetic nerves. In the heart ATP has been shown to cause a pronounced positive inotropic effect and may also act in synergy with beta-adrenergic agonists to augment cardiomyocyte contractility. The aim of the present study was to investigate the inotropic effects mediated by purinergic P2 receptors using isolated mouse cardiomyocytes. Stable adenine nucleotide analogs were used and the agonist rank order for adenine nucleotide stimulation of the mouse cardiomyocytes was AR-C67085>ATPgammaS>2-MeSATP>>>2-MeSADP=0, that fits the agonist profile of the P2Y11 receptor. ATPgammaS induced a positive inotropic response in single mouse cardiomyocytes. The response was similar to that for the beta1 receptor agonist isoproterenol. The most potent response was obtained using AR-C67085, a P2Y11 receptor agonist. This agonist also potentiated contractions in isolated trabecular preparations. The adenylyl cyclase blocker (SQ22563) and phospholipase C (PLC) blocker (U73122) demonstrated that both pathways were required for the inotropic response of AR-C67085. A cAMP enzyme immunoassay confirmed that AR-C67085 increased cAMP in the cardiomyocytes. These findings are in agreement with the P2Y11 receptor, coupled both to activation of IP3 and cAMP, being a major receptor for ATP induced inotropy. Analyzing cardiomyocytes from desmin deficient mice, Des-/-, with a congenital cardiomyopathy, we found a lower sensitivity to AR-C67085, suggesting a down-regulation of P2Y11 receptor function in heart failure. The prominent action of the P2Y11 receptor in controling cardiomyocyte contractility and possible alterations in its function during cardiomyopathy may suggest this receptor as a potential therapeutic target. It is possible that agonists for the P2Y11 receptor could be used to improve cardiac output in patients with circulatory shock and that P2Y11 receptor antagonist could be beneficial in patients with congestive heart failure (CHF).
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PMID:Phospholipase C and cAMP-dependent positive inotropic effects of ATP in mouse cardiomyocytes via P2Y11-like receptors. 1589 64

Beta-adrenergic receptor signaling, desensitization, and downregualtion are fundamental mechanisms that contribute to both normal and altered myocardial function. The development of pharmacological and biochemical assays has provided the ability to measure alterations both in adrenergic receptor density and the subsequent coupling of adrenergic receptors downstream effectors, namely, adenylyl cyclase. Furthermore, transthoracic echocardiography of the murine heart has provided insight into changes in cardiac physiology that accompany altered adrenergic receptor signaling. The protocols described within this chapter provide the means to quantify beta-adrenergic density, measure adenylyl cyclase activity, and evaluate cardiac hypertrophy to better understand the mechanisms responsible for cardiac hypertrophy and heart failure.
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PMID:Methods for the detection of altered beta-adrenergic receptor signaling pathways in hypertrophied hearts. 1601 29


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