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)

beta-Adrenergic receptors are often studied as prototypes of the large family of G-protein-coupled receptors, which includes many other well-known members such as the muscarinic acetylcholine receptors, but also the receptors for light, taste and olfaction. These receptors are regulated by multiple mechanisms which can affect either their function or their expression to a rapidly changing environment. The most obvious changes are effected by receptor agonists, and this process is called receptor desensitization. On the functional level, the most intriguing and important mechanism of desensitization involves the phosphorylation of beta-adrenergic and homologous receptors by specific receptor kinases, termed the G-protein-coupled receptor kinases (GRKs). This phosphorylation is followed by binding of arrestins to the receptors, which causes uncoupling of receptors and G-proteins and thus results in a loss of receptor function. On the expression level, there appear to be two major pathways leading to a reduction of the receptor number: degradation of the receptors themselves, or reduced receptor synthesis brought about by reduced receptor mRNA levels. Heart failure is accompanied by a markedly reduced responsiveness of the beta-adrenergic receptor system, which in many ways resembles the phenomena seen in agonist-induced receptor desensitization. The levels of beta 1-adrenergic receptors are reduced, and this reduction is paralleled by similar decreases in the levels of the corresponding mRNA. At the same time, the activity and the mRNA levels of one of the GRK-isoforms, GRK2 (which is identical to the beta-adrenergic receptor kinase 1) are increased. These alterations may contribute to the loss of beta-adrenergic receptor responsiveness in heart failure and result in further impairment of cardiac function.
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PMID:Mechanisms of beta-adrenergic receptor desensitization: from molecular biology to heart failure. 895 41

Transgenic mice were generated with cardiac-specific overexpression of the wild-type (WT) alpha1B-adrenergic receptor (AR) using the murine alpha-myosin heavy chain gene promoter. Previously, we described transgenic mice with alpha-myosin heavy chain-directed expression of a constitutively active mutant alpha1B-AR that had a phenotype of myocardial hypertrophy (Milano, C. A., Dolber, P. C., Rockman, H. A., Bond, R. A., Venable M. E., Allen, L. F., and Lefkowitz, R. J. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 10109-10113). In animals with >40-fold WT alpha1-AR overexpression, basal myocardial diacylglycerol content was significantly increased, indicating enhanced alpha1-adrenergic signaling and phospholipase C activity. In contrast to the mice overexpressing constitutively active mutant alpha1B-ARs, the hearts of these mice did not develop cardiac hypertrophy despite an 8-fold increase in ventricular mRNA for atrial natriuretic factor. In vivo physiology was studied in anesthetized intact animals and showed left ventricular contractility in response to the beta-agonist isoproterenol to be significantly depressed in animals overexpressing WT alpha1B-ARs. Membranes purified from the hearts of WT alpha1BAR-overexpressing mice demonstrated significantly attenuated adenylyl cyclase activity basally and after stimulation with isoproterenol, norepinephrine, or phenylephrine. Interestingly, these in vitro changes in signaling were reversed after treating the mice with pertussis toxin, suggesting that the extraordinarily high levels of WT alpha1B-ARs can lead to coupling to pertussis toxin-sensitive G proteins. Another potential contributor to the observed decreased myocardial signaling and function could be enhanced beta-AR desensitization as beta-adrenergic receptor kinase (betaARK1) activity was found to be significantly elevated (>3-fold) in myocardial extracts isolated from WT alpha1B-AR-overexpressing mice. This type of altered signal transduction may become critical in disease conditions such as heart failure where betaARK1 levels are elevated and beta-ARs are down-regulated, leading to a higher percentage of cardiac alpha1-ARs. Thus, these mice serve as a unique experimental model to study the in vivo interactions between alpha- and beta-ARs in the heart.
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PMID:Transgenic mice with cardiac overexpression of alpha1B-adrenergic receptors. In vivo alpha1-adrenergic receptor-mediated regulation of beta-adrenergic signaling. 926 Nov 35

We examined alterations in left ventricular (LV) G protein receptor kinase (GRK) and adenylyl cyclase (AC) isoform expression during the development of pacing-induced congestive heart failure (CHF). AC isoform and GRK expression were assessed 4 (mild CHF) and 28 (severe CHF) days after initiation of pacing. LV beta-adrenergic receptor (beta-AR) number and G protein content were unchanged by mild CHF. LV AC isoform mRNA content was unaltered by mild CHF, but there were increases in total GRK activity (P < 0.01), total GRK5 protein content (P < 0.04), and GRK5 mRNA (P = 0.003); total GRK2 protein content and GRK2 mRNA were unchanged. Mild CHF was associated with decreased beta-AR coupling (P < 0.01) and reduced beta-AR stimulation of AC (P < 0.05). Severe CHF was associated with LV beta-AR downregulation (P = 0.0001) and uncoupling (P < 0.001) and marked generalized reduction of AC activity (mean P = 0.01). LV ACVI isoform mRNA content was reduced (P = 0.002), but ACII and ACV isoform mRNA contents were unaffected. Persistent elevations in LV total GRK activity (P < 0.01), total GRK5 protein content (P < 0.001), and GRK5 mRNA (P = 0.01) were found; in contrast, total GRK2 protein content was unchanged and GRK2 mRNA was reduced (P = 0.02). These studies indicate that increased GRK activity is an early charge in heart failure that predates alterations in AC isoform expression. Impaired hormonal stimulation of AC, associated with beta-AR uncoupling, may result from increased GRK5 expression. AC downregulation is isoform specific and accompanies severe but not mild CHF.
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PMID:Adenylyl cyclase and G protein receptor kinase expression during development of heart failure. 927 87

A strong sympathetic activation has been observed in heart failure and is the cause of beta-adrenergic desensitization in this condition. On the receptor level there is downregulation of beta1-adrenergic receptors and uncoupling of beta2-adrenoceptors. The latter mechanism has been related to an increased activity and gene expression of beta-adrenoceptor kinase in failing myocardium, leading to phosphorylation and uncoupling of receptors. beta3-Adrenoceptors mediate negative inotropic effects, but alterations in these receptors are not known. In addition, an increase in inhibitory G protein alpha subunits (Gi alpha) has been suggested to be causally linked to adenylyl cyclase desensitization in heart failure. In contrast, the catalytic subunit of adenylyl cyclase, stimulatory G protein alpha and betagamma subunits, have been observed to be unchanged. Recent evidence shows that increases in Gi alpha also depress adenylyl cyclase in compensated cardiac hypertrophy both in monogenic and polygenic and in secondary hypertension. These increases of Gi alpha can suppress adenylyl cyclase in the absence of beta-adrenergic receptor downregulation. Since cardiac hypertrophy in pressure overload is a strong predictor of cardiac failure, these observations indicate that adenylyl cyclase desensitization by Gi alpha may be a pathophysiologically relevant mechanism contributing to the progression from compensated cardiac hypertrophy to heart failure.
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PMID:Beta-adrenergic signal transduction in the failing and hypertrophied myocardium. 942 16

Heart failure is accompanied by severely impaired beta-adrenergic receptor (betaAR) function, which includes loss of betaAR density and functional uncoupling of remaining receptors. An important mechanism for the rapid desensitization of betaAR function is agonist-stimulated receptor phosphorylation by the betaAR kinase (betaARK1), an enzyme known to be elevated in failing human heart tissue. To investigate whether alterations in betaAR function contribute to the development of myocardial failure, transgenic mice with cardiac-restricted overexpression of either a peptide inhibitor of betaARK1 or the beta2AR were mated into a genetic model of murine heart failure (MLP-/-). In vivo cardiac function was assessed by echocardiography and cardiac catheterization. Both MLP-/- and MLP-/-/beta2AR mice had enlarged left ventricular (LV) chambers with significantly reduced fractional shortening and mean velocity of circumferential fiber shortening. In contrast, MLP-/-/betaARKct mice had normal LV chamber size and function. Basal LV contractility in the MLP-/-/betaARKct mice, as measured by LV dP/dtmax, was increased significantly compared with the MLP-/- mice but less than controls. Importantly, heightened betaAR desensitization in the MLP-/- mice, measured in vivo (responsiveness to isoproterenol) and in vitro (isoproterenol-stimulated membrane adenylyl cyclase activity), was completely reversed with overexpression of the betaARK1 inhibitor. We report here the striking finding that overexpression of this inhibitor prevents the development of cardiomyopathy in this murine model of heart failure. These findings implicate abnormal betaAR-G protein coupling in the pathogenesis of the failing heart and point the way toward development of agents to inhibit betaARK1 as a novel mode of therapy.
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PMID:Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice. 961 28

We studied the effect of alterations in the level of myocardial beta-adrenergic receptor kinase betaARK1) in two types of genetically altered mice. The first group is heterozygous for betaARK1 gene ablation, betaARK1(+/-), and the second is not only heterozygous for betaARK1 gene ablation but is also transgenic for cardiac-specific overexpression of a betaARK1 COOH-terminal inhibitor peptide, betaARK1(+/-)betaARKct. In contrast to the embryonic lethal phenotype of the homozygous betaARK1 knockout (Jaber, M., Koch, W. J., Rockman, H. A., Smith, B., Bond, R. A., Sulik, K., Ross, J., Jr., Lefkowitz, R. J., Caron, M. G., and Giros, B. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 12974-12979), betaARK1(+/-) mice develop normally. Cardiac catheterization was performed in mice and showed a stepwise increase in contractile function in the betaARK1(+/-) and betaARK1(+/-)betaARKct mice with the greatest level observed in the betaARK1(+/-)betaARKct animals. Contractile parameters were measured in adult myocytes isolated from both groups of gene-targeted animals. A significantly greater increase in percent cell shortening and rate of cell shortening following isoproterenol stimulation was observed in the betaARK1(+/-) and betaARK1(+/-)betaARKct myocytes compared with wild-type cells, indicating a progressive increase in intrinsic contractility. These data demonstrate that contractile function can be modulated by the level of betaARK1 activity. This has important implications in disease states such as heart failure (in which betaARK1 activity is increased) and suggests that betaARK1 should be considered as a therapeutic target in this situation. Even partial inhibition of betaARK1 activity enhances beta-adrenergic receptor signaling leading to improved functional catecholamine responsiveness.
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PMID:Control of myocardial contractile function by the level of beta-adrenergic receptor kinase 1 in gene-targeted mice. 966 Jul 78

A number of molecular and cellular alterations have been identified in the failing human heart that help to understand contraction and relaxation abnormalities. Cyclic AMP dependent pathways are desensitized due to quantitative changes in beta-adrenoceptors, beta-adrenoceptor kinase, and inhibitory G-proteins. Calcium homeostasis is impaired, characterized by a decreased calcium reuptake rate of the sarcoplasmic reticulum, an increased threshold of the calcium release channel, and an increased Na+/Ca2+ exchanger expression. Myofibrillar function may be affected by a decrease in Mg2(+)-ATPase activity and in troponin I phosphorylation, and by changes in TnT isoform expression. These alterations seem to occur independently of the underlying etiology of heart failure and are most likely consequences rather than primary causes of the disease. Most likely, chronic neurohumoral activation and abnormal mechanical load initiate the majority of the hitherto known changes in the myocardium and promote the further progression of cardiac failure as part of a vicious circle. Further extension of knowledge of pathophysiological mechanisms should improve therapeutical strategies which aim at slowing the progression of heart failure and at reversing secondary alterations by interrupting the deleterious influence of neurohumoral activation. Future progress will depend on answers to current gaps in our knowledge of heart failure, including the unknown primary cause of idiopathic dilated cardiomyopathy, factors underlying the greatly variable progression of pump failure, as well as the exact pathophysiological role of the molecular alterations as described in this review.
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PMID:Cellular and molecular aspects of contractile dysfunction in heart failure. 979 11

In heart failure, a strong sympathetic activation has been observed and is regarded as the cause of beta-adrenergic desensitization in this condition. On the receptor level, there is a down-regulation of beta1-adrenergic receptors. In myocardium of patients on catecholamine treatment, the number of beta-adrenergic receptors can be further reduced. An uncoupling of beta2-adrenoceptors has been related to an increased activity and gene expression of beta-ARK in failing myocardium leading to phosphorylation and uncoupling of receptors. Beta3-adrenoceptors mediate negative inotropic effects, but alterations of these receptors are not known. In addition, an increase of inhibitory G-protein alpha-subunits (Gialpha) has been suggested to be causally linked to adenylyl cyclase desensitization in heart failure. In contrast, the catalytic subunit of adenylyl cyclase, stimulatory G-protein alpha-subunits and betagamma-subunits have been observed to be unchanged. In patients with catecholamine-refractory septic or cardiogenic shock, an increase of Gialpha has been observed and related to the reduced effects of catecholamines in these conditions. The discovered mechanisms set the stage for the development of alternative strategies to increase force of contraction like the combination of PDE-inhibitors and catecholamines or Ca2+ sensitizing agents.
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PMID:Catecholamine refractoriness and their mechanisms in cardiocirculatory shock and chronic heart failure. 982 78

We studied alterations in the beta-adrenergic receptor (beta-AR) system of rabbit hearts during the development of heart failure (HF) after myocardial infarction (MI) to determine whether the molecular beta-AR abnormalities associated with human HF exist in this animal model. Rabbit HF was established 3 wk after left circumflex coronary artery (LCX) ligation by in vivo physiological measurements, and molecular beta-AR signaling was examined in tissue and cultured ventricular myocytes. We found that there was a significant global reduction in beta-AR density by approximately 50% in both ventricles of MI animals compared with sham-operated control animals and that functional beta-AR coupling was significantly reduced. Importantly, as found in human HF, myocardial protein levels and activity of the beta-AR kinase (beta-ARK1) and Galphai were found to be significantly elevated in MI rabbits, suggesting that these molecules are contributing to myocardial dysfunction. Thus the myocardial beta-AR system of this rabbit model of HF shares important biochemical characteristics with human HF and therefore is an ideal laboratory model to investigate novel therapeutic targets for the treatment of HF.
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PMID:Molecular beta-adrenergic signaling abnormalities in failing rabbit hearts after infarction. 1036 63

Cardiac beta(2)-adrenergic receptor (beta(2)AR) overexpression is a potential contractile therapy for heart failure. Cardiac contractility was elevated in mice overexpressing beta(2)ARs (TG4s) with no adverse effects under normal conditions. To assess the consequences of beta(2)AR overexpression during ischemia, perfused hearts from TG4 and wild-type mice were subjected to 20-minute ischemia and 40-minute reperfusion. During ischemia, ATP and pH fell lower in TG4 hearts than wild type. Ischemic injury was greater in TG4 hearts, as indicated by lower postischemic recoveries of contractile function, ATP, and phosphocreatine. Because beta(2)ARs, unlike beta(1)ARs, couple to G(i) as well as G(s), we pretreated mice with the G(i) inhibitor pertussis toxin (PTX). PTX treatment increased basal contractility in TG4 hearts and abolished the contractile resistance to isoproterenol. During ischemia, ATP fell lower in TG4+PTX than in TG4 hearts. Recoveries of contractile function and ATP were lower in TG4+PTX than in TG4 hearts. We also studied mice that overexpressed either betaARK1 (TGbetaARK1) or a betaARK1 inhibitor (TGbetaARKct). Recoveries of function, ATP, and phosphocreatine were higher in TGbetaARK1 hearts than in wild-type hearts. Despite basal contractility being elevated in TGbetaARKct hearts to the same level as that of TG4s, ischemic injury was not increased. In summary, beta(2)AR overexpression increased ischemic injury, whereas betaARK1 overexpression was protective. Ischemic injury in the beta(2)AR overexpressors was exacerbated by PTX treatment, implying that it was G(s) not G(i) activity that enhanced injury. Unlike beta(2)AR overexpression, basal contractility was increased by betaARK1 inhibitor expression without increasing ischemic injury, thus implicating a safer potential therapy for heart failure.
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PMID:Overexpression of the cardiac beta(2)-adrenergic receptor and expression of a beta-adrenergic receptor kinase-1 (betaARK1) inhibitor both increase myocardial contractility but have differential effects on susceptibility to ischemic injury. 1057 39


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