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)

G protein coupled receptors or serpentine receptors work as signalling switches that turn extracellular signals into activation of multiple molecules at the intracellular face of the plasma membrane. Serpentine receptors are the targets of around 70% of all current drugs in clinical medicine. We suggest that these receptors can be pharmacologically targeted by modification of their unique internal inhibitors the G protein coupled receptor kinases (GRKs). The GRKs constitute a family of serine/threonine kinases that specifically bind to and phosphorylate agonist-activated serpentine receptors. The phosphorylated receptors are recognized by arrestins that bind to the receptor and uncouple them from attached G proteins thereby terminating G protein signalling. This review focuses on a ubiquitously expressed GRK family member dubbed GRK2 (previously called beta-adrenergic receptor kinase 1) that regulates cellular signalling at multiple levels. In Gq-coupled signalling modules GRK2 may function as a feedback inhibitor molecule that monitors, inhibits and re-directs the information flow. GRK2 acts as a negative feedback protein by interacting with at least six key signalling molecules in the Gq pathway including; receptors, free G beta gamma subunits, activated G alpha q subunits, phosphatidylinositol-4, 5-bisphosphate (PIP2), protein kinase C (PKC) and calmodulin (CaM). GRK signalling is important for immune, endocrine and cardiovascular function manifesting itself in disorders such as heart failure and lymphocyte activation especially in chronic inflammation. This review summarizes the advances made in understanding the many actions of GRKs and addresses their potential as novel therapeutic targets.
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PMID:G protein-coupled receptor kinase 2--a feedback regulator of Gq pathway signalling. 1247 95

Chronic stimulation of beta2-receptors with beta2-agonists causes desensitisation, which in skeletal muscle is accompanied by myosin heavy chain (MHC) remodelling, similar to that observed in heart failure patients. However, the mechanisms for this skeletal muscle remodelling are not well established. G protein-coupled receptor kinases (GRKs) specifically phosphorylate and desensitise G protein-coupled receptors during periods of agonist activation. However, desensitisation associated with prolonged agonist activation alters beta-adrenergic signalling, and downstream affects gene expression. We hypothesised that skeletal muscle remodelling induced by beta2-agonist administration could be regulated by GRK expression. Therefore the aim of this study was firstly to characterise which, if any, of the six known isoforms of GRK were expressed in skeletal muscle and then secondly to determine whether remodelled skeletal muscle induced by chronic beta2-agonist administration was accompanied by altered expression of GRK isoforms. Male Wistar rats were administered a beta2-agonist daily for 8 weeks, and the expression of MHC and GRKs examined in gastrocnemius and soleus muscles. Treatment with beta2-agonist caused a change in MHC in soleus from types I to IIA, and in gastrocnemius from MHC types IIA/IIX to IIB. Western blotting revealed that GRK2 and GRK5 were expressed in skeletal muscle. Furthermore, despite changes in MHC and differential muscle-specific expression of GRK isoforms, there was no significant change in expression of GRK2 and GRK5 in soleus or gastrocnemius following beta2-agonist administration. In conclusion the level of GRK expression is unlikely to be responsible for MHC switching following chronic beta2-receptor stimulation.
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PMID:G protein-coupled receptor kinases 2 and 5 are differentially expressed in rat skeletal muscle and remain unchanged following beta2-agonist administration. 1262 33

Heart failure (HF) remains a significant and increasing cause of worldwide morbidity and mortality. HF is less a disease than a common clinical endpoint resulting from diverse, but often co-existing etiologies-including hypertension, coronary artery disease, and viral cardiomyopathy. Regardless of the pathologic trigger, HF can be characterized by a series of specific, molecular changes in the diseased myocardium. Noteworthy among these changes are alterations in the beta-adrenergic receptor (betaAR) signaling cascade. betaARs belong to the larger family of G-protein-coupled receptors (GPCRs) and modulate cardiac function by controlling the inotropic and chronotropic response to catecholamines. betaARs, in turn, are regulated by GPCR kinases (GRKs). GRKs phosphorylate betaARs, blocking downstream-signaling cascades and ultimately desensitizing the receptor to further catecholamine stimuli. Recent advances in transgenic mouse and gene therapy techniques have led to therapeutic strategies by manipulating betaAR signaling, specifically through the inhibition of the beta-adrenergic receptor kinase (betaARK1 or GRK2), the predominant myocardial GRK. The purpose of this manuscript, then, is to review (1). the changes that occur to betaAR-signaling pathways in HF, (2). the evidence from transgenic murine studies examining the consequences of betaARK1 manipulation in the failing heart, and (3). the effectiveness of in vivo applications of betaARK1-targeted gene therapy at ameliorating HF.
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PMID:The beta-adrenergic receptor kinase in heart failure. 1451 24

Heart failure represents the endpoint to many triggering cardiovascular pathologies. However, there are molecular and biochemical features that remain common to the failing heart, despite the varying etiologies. Principal among these is heightened activation of the sympathetic nervous system and associated enhancement of adrenergic signaling pathways via the catecholamines, norepinephrine and epinephrine. During heart failure, several hallmark alterations in the adrenergic system contribute to loss of cardiac function. To specifically study these changes in a physiologically relevant setting, we and others have utilized advances in genetically engineered mouse technology. This chapter will discuss the many transgenic and knockout mouse models that have been developed to study the adrenergic system in the normal and failing heart. These models include genetically manipulated alterations of adrenergic receptors, linked heterotrimeric G proteins, and the regulatory G protein-coupled receptor kinases (GRKs). Among the more-interesting information gained from these models is the finding that inhibition of a particular GRK - GRK2 or beta adrenergic receptor kinase 1 (betaARK1) - is a potential novel therapeutic strategy to improve function in the setting of heart failure. Furthermore, we will discuss recent transgenic research that proposes an important role for hypertension in the development of heart failure. Overall, genetically engineered mouse models pertaining to this critical myocardial signaling system have provided novel insight into heart function under normal conditions and during states of dysfunction and failure.
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PMID:The adrenergic pathway and heart failure. 1474 95

In the heart, beta -adrenergic receptors (beta ARs), members of the superfamily of G protein-coupled receptors (GPCRs), modulate cardiac responses to catecholamines. beta AR signaling, which is compromised in many cardiac diseases (e.g., congestive heart failure), is regulated by GPCR kinases (GRKs). Levels of the most abundant cardiac GRK, known as GRK2 or beta AR kinase 1 (beta ARK1), are increased in both animal and human heart failure. Transgenic mouse models have demonstrated that beta ARK1 plays a vital role in cardiac function and development, as well as in the regulation of myocardial signaling, and pharmacological studies have further implicated GRKs in the impairment of cardiac GPCR signaling. Gene therapy, along with the development of small-molecule modulators of GRK activity, has indicated in multiple animal models that the manipulation of GRK activity may elicit therapeutic benefits in many forms of cardiac disease.
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PMID:Phosphorylation of G protein-coupled receptors: GPCR kinases in heart disease. 1499 40

GRKs critically regulate betaAR signaling via receptor phosphorylation and the triggering of desensitization. In the heart, betaARs control the chronotropic, lusitropic, and inotropic responses to the catecholamine neurotransmitters, norepinephrine and epinephrine. Signaling through cardiac betaARs is significantly impaired in many cardiovascular disorders, including congestive heart failure. betaARK1 (also known as GRK2) is the most abundant GRK in the heart, and it is increased in several cardiovascular diseases associated with impaired cardiac signaling and function, suggesting that this molecule could have pathophysiological relevance in the setting of heart failure. The ability to manipulate the mouse genome has provided a powerful tool to study the physiological implications of altering GRK activity and expression in the heart. Recent studies in several different mouse models have demonstrated that betaARK1 plays a key role not only in the regulation of myocardial signaling, but also in cardiac function and development. Moreover, studies have shown that targeting the activity of GRKs, especially betaARK1, appears to be a novel therapeutic strategy for the treatment of the failing heart. Gene therapy technology makes it possible, beyond what is possible in the mouse, to directly test in larger animals whether betaARK1 inhibition in the setting of disease will improve the function of the compromised heart, and this methodology has also lead to compelling results. These genetic approaches or the development of small molecule inhibitors of betaARK1 and GRK activity may advance therapeutic options for heart disease.
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PMID:Transgenic mice targeting the heart unveil G protein-coupled receptor kinases as therapeutic targets. 1509 Feb

Heart failure (HF) represents one of the leading causes of morbidity and mortality in developed nations today. Although this disease process represents a final common endpoint for several entities, including hypertension, coronary artery disease, and cardiomyopathy, a predominant characteristic of end-stage HF is an altered beta-adrenergic receptor signaling cascade. In the heart, beta-adrenergic receptors (beta ARs), members of the superfamily of G-protein-coupled receptors (GPCRs), modulate cardiac function by controlling chronotropic, inotropic, and lusitropic responses to catecholamines of the sympathetic nervous system. In HF, beta ARs are desensitized and downregulated in a maladaptive response to chronic stimulation. This process is largely mediated by G-protein-coupled receptor kinases (GRKs), which phosphorylate GPCRs leading to functional uncoupling. The most abundant cardiac GRK, known as GRK2 or beta AR kinase 1 (beta ARK1), is increased in human HF, and has been implicated in the pathogenesis of dysfunctional cardiac beta AR signaling. The association of beta ARs and GRKs with impaired cardiac function has been extensively studied using transgenic mouse models, which have demonstrated that beta ARK1 plays a vital role in the regulation of myocardial beta AR signaling. These findings have caused beta ARs and GRKs to be regarded as potential therapeutic targets, and gene therapy strategies have been used to manipulate the beta AR signaling pathway in myocardium, leading to improved function in the compromised heart. Ultimately, these genetic modifications of the heart may represent new potential therapies for human HF.
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PMID:Genetic manipulation of myocardial beta-adrenergic receptor activation and desensitization. 1524 31

Heart failure is a leading cause of hospitalization worldwide. No major significant improvements in prognosis have been achieved for heart failure over the last several decades despite advances in disease management. Heart failure itself represents a final common endpoint for several disease entities, including hypertension and coronary artery disease. On a molecular level, certain biochemical features remain common to failing myocardium. Among these are alterations in the beta-adrenergic receptor (beta-AR) signaling cascade. Recent advances in transgenic and gene therapy techniques have presented novel therapeutic strategies for management of heart failure via genetic manipulation of beta-AR signaling including the targeted inhibition of the beta-AR kinase (betaARK1 or GRK2). In this review, we will discuss the beta-AR signaling changes that accompany heart failure as well as corresponding therapeutic strategies. We will then review the evidence from transgenic mouse work supporting the use of beta-AR manipulation in the failing heart and more recent in vivo applications of gene therapy directed at reversing or preventing heart failure.
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PMID:Genetic and phenotypic targeting of beta-adrenergic signaling in heart failure. 1552 62

G-protein-coupled receptor kinases (GRKs) are involved in cardiac hypertrophy and failure. But their temporal expression and cellular localization during the development of hypertrophy and its transition to failure remains to be investigated. In this study, we determined the expression and subcellular distribution of GRK2, GRK3, GRK5, and GRK6 in cardiac myocytes of 2- to 24-month-old spontaneously hypertensive heart failure (SHHF) rats. GRK2 increased in the intercalated disks in 6-, 12-, and 24-month-old SHHF rats, although total expression remained relatively constant from 2 to 24 months in both SHHF and normotensive rats. GRK3 expression progressively increased in 6-, 12-, and 24-month-old SHHF rats and was significantly higher than in age-matched controls. Immunolabeling of GRK3 showed a typical pattern of cross-striations that colocalized with alpha-actinin and G(alphas) at Z-lines in both SHHF and control rats. GRK5 expression showed no change from 2 to 24 months in both SHHF and normotensive rats. Confocal analysis revealed nuclear translocation of GRK5 in myocytes of SHHF rats. GRK6 had a striated pattern colocalized with alpha-actinin at Z-lines in the cytoplasm and was also present in the intercalated disks of cardiac myocytes from both SHHF and control rats. GRK6 expression increased in 12- and 24-month-old SHHF rats and was significantly higher than in age-matched controls. GRK6 labeling was reduced at the intercalated disks, but increased in the cytoplasm of cardiac myocytes from SHHF rats compared to age-matched controls. The increased expression of GRK3 and GRK6 and subcellular redistribution of GRK2, GRK5, and GRK6 in SHHF rats may be involved in abnormal remodeling of cardiac myocytes in hypertensive hypertrophy and failure.
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PMID:Myocardial expression and redistribution of GRKs in hypertensive hypertrophy and failure. 1558 34

To examine the mechanisms of changes in beta-adrenergic signal transduction in heart failing due to volume overload, we studied the status of beta-adrenoceptors (beta-ARs), G protein-coupled receptor kinase (GRK), and beta-arrestin in heart failure due to aortocaval shunt (AVS). Heart failure in rats was induced by creating AVS for 16 wk, and beta-AR binding, GRK activity, as well as their protein content, and mRNA levels were determined in both left and right ventricles. The density and protein content for beta1-ARs, unlike those for beta2-ARs, were increased in the failing hearts. Furthermore, protein contents for GRK isoforms and beta-arrestin-1 were decreased in membranous fractions and increased in cytosolic fractions from the failing hearts. On the other hand, steady-state mRNA levels for beta1-ARs and GRK2, as well as protein content for Gbetagamma-subunits, did not change in the failing heart. Basal cardiac function was depressed; however, both in vivo and ex vivo positive inotropic responses of the failing hearts to isoproterenol were augmented. Treatment of AVS animals with imidapril (1 mg.kg(-1).day(-1)) or losartan (20 mg.kg(-1).day(-1)) retarded the progression of heart failure; partially prevented changes in beta1-ARs, GRKs, and beta-arrestin-1 in the failing myocardium; and attenuated the increase in positive inotropic effect of isoproterenol. These results indicate that upregulation of beta1-ARs is associated with subcellular redistribution of GRKs and beta-arrestin-1 in the failing heart due to volume overload. Furthermore, attenuation of alterations in beta-adrenergic system by imidapril or losartan may be due to blockade of the renin-angiotensin system in the AVS model of heart failure.
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PMID:Upregulation of beta-adrenergic receptors in heart failure due to volume overload. 1573 91


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