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)

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

While an age-associated diminution in myocardial contractile response to beta-adrenergic receptor (beta-AR) stimulation has been widely demonstrated to occur in the context of increased levels of plasma catecholamines, some critical mechanisms that govern beta-AR signaling must still be examined in aged hearts. Specifically, the contribution of beta-AR subtypes (beta1 versus beta2) to the overall reduction in contractile response with aging is unknown. Additionally, whether G protein-coupled receptor kinases (GRKs), which mediate receptor desensitization, or adenylyl cyclase inhibitory G proteins (Gi) are increased with aging has not been examined. Both these inhibitory mechanisms are upregulated in chronic heart failure, a condition also associated with diminished beta-AR responsiveness and increased circulatory catecholamines. In this study, the contractile responses to both beta1-AR and beta2-AR stimulation were examined in rat ventricular myocytes of a broad age range (2, 8, and 24 mo). A marked age-associated depression in contractile response to both beta-AR subtype stimulation was observed. This was associated with a nonselective reduction in the density of both beta-AR subtypes and a reduction in membrane adenylyl cyclase response to both beta-AR subtype agonists, NaF or forskolin. However, the age-associated diminutions in contractile responses to either beta1-AR or beta2-AR stimulation were not rescued by inhibiting Gi with pertussis toxin treatment. Further, the abundance or activity of beta-adrenergic receptor kinase, GRK5, or Gi did not significantly change with aging. Thus, we conclude that the positive inotropic effects of both beta1- and beta2-AR stimulation are markedly decreased with aging in rat ventricular myocytes and this is accompanied by decreases in both beta-AR subtype densities and a reduction in membrane adenylate cyclase activity. Neither GRKs nor Gi proteins appear to contribute to the age-associated reduction in cardiac beta-AR responsiveness.
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PMID:Age-associated reductions in cardiac beta1- and beta2-adrenergic responses without changes in inhibitory G proteins or receptor kinases. 950 68

We have previously shown that left ventricular (LV) pacing-induced heart failure is associated with preserved wall thickening in the interventricular septum (IVS) compared with the posterolateral wall (PLW). The current study focuses on the relationship between regional myocardial function and altered beta-adrenergic receptor (beta-AR) signaling. We studied 15 pigs: 6 controls and 9 paced from the left ventricle (225 beats/min, 26 +/- 3 days). Heart failure was documented by decreased LV fractional shortening (P < 0.0001) and increased left atrial pressure (P < 0.0001). In heart failure, despite marked differences in basal regional function (percent wall thickening: IVS, 33 +/- 10% vs. PLW, 13 +/- 7%; P = 0.0003), there were no differences between the two regions in beta-AR responsiveness, measured by regional wall thickening in response to dobutamine infusion and any measurement of adrenergic signaling. Adenylyl cyclase activity, beta-AR number, and beta-AR/Gs coupling were markedly reduced in failing LV without regional differences. In animals with heart failure, LV G protein receptor kinase (GRK) isoform 2 content was unchanged and GRK5, the other major GRK isoform, was increased more than threefold (IVS, 0.51 +/- 0.20 vs. 0. 12 +/- 0.12 arbitrary densitometric units, P = 0.01; PLW, 0.47 +/- 0. 15 vs. 0.13 +/- 0.09 arbitrary densitometric units, P = 0.03), but again, there were no regional differences. These data indicate that systemic rather than regional factors govern LV adrenergic signaling and that regional adrenergic signaling abnormalities poorly predict wall thickening in the same regions.
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PMID:Dissociation between regional dysfunction and beta-adrenergic receptor signaling in heart failure. 974 75

-Responsiveness to beta-adrenergic stimulation is reduced in the failing human myocardium. This results principally from reduced beta-adrenergic receptor (betaAR) density, elevated beta-adrenergic receptor kinase 1 (betaARK1) levels, and functional uncoupling of remaining receptors. The temporal nature of changes in the human myocardial beta-adrenergic system relative to onset of symptomatic heart failure (HF) has been difficult to discern. A relatively new model of HF, the spontaneously hypertensive heart failure (SHHF) rat spontaneously and reproducibly develops left ventricular hypertrophy (LVH) and progresses to HF, thus enabling longitudinal studies to examine the cellular and molecular bases for hypertension-induced cardiac hypertrophy and subsequent HF. The purpose of this study was to examine age-dependent changes in the betaAR system in this model. Lean male SHHF rats at 3, 7, 14, and 20 months were compared with age-matched Sprague-Dawley (SD) control rats ([C]; 4 animals/group). At all ages the SHHF rats had elevated blood pressures and left ventricular end-diastolic pressure relative to the SD control rats (P<0.05). Compared with age-matched SD control rats, LVH was evident by 3 months in SHHF rats; 20-month-old SHHF rats had significantly greater LVH compared with the other SHHF rat groups. beta-adrenergic responsiveness (maximal heart rate to isoproterenol) was reduced only in 20-month-old SHHF rats. betaARK1 protein levels and activity were elevated at 14 months (162+/-10% and 195+/-20% C, respectively), and betaARK1 protein remained elevated at 20 months (140+/-14% C). In contrast, G protein-coupled receptor kinase 5, a second receptor kinase in the heart, remained unchanged at all ages. betaAR density did not change with age in the SD control rats and was similar in the SHHF rats until 20 months of age when the receptor number was reduced (30+/-1%). These data indicate that cardiac dysfunction is coincident with reduced betaAR density. Importantly, cardiac dysfunction was preceded by elevated betaARK1 levels and activity, thus suggesting that betaARK1 may be a precipitating factor in the transition from hypertension-induced compensatory cardiac hypertrophy to HF. Furthermore, these results indicate that the SHHF rat is a powerful model for use in examination of the mechanisms involved in alterations of beta-adrenergic signaling that occur in human HF.
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PMID:The myocardial beta-adrenergic system in spontaneously hypertensive heart failure (SHHF) rats. 993 Nov 37

1. Studies using animal experimental models have suggested that the beta2-adrenoceptor is uncoupled in association with alterations in the expression of G-protein-coupled receptor kinases (GRK) 2/3 in heart failure. However, the functional expression of the components of this pathway in human disease has not been fully elucidated yet. In the present study, we evaluated the possibility that the regulation of beta2-adrenoceptor signalling components in patients with left ventricular volume overload (VOL) depends on the severity of the overload. 2. We characterized the lymphocyte GRK 2-6, beta-arrestins 1 and 2, beta2-adrenoceptor expression at the mRNA and protein levels, as well as the activity of adenylyl cyclase, protein kinases (PK) A and PKC in patients with VOL using healthy blood donors as controls. 3. In the patient group, GRK2 mRNA was increased by 61% (P < 0.001), GRK3 was increased by 54% (P < 0.005), GRK5 was increased fivefold (P < 0.001) and the beta-arrestin 2 mRNA was increased by 40% (P < 0.05). These increases were paralleled with a sixfold increase in GRK2, a twofold increase in GRK3 and a 1.3-fold increase in GRK5 protein levels. These changes were associated with a significant decrease in beta2-adrenoceptor mRNA, the basal, catalytic and receptor-mediated activity of adenylyl cyclase and sensitization of the forskolin-stimulated activity towards augmented inhibition by guanylimidodiphosphate. In general, the increase in GRK2 and 5 mRNA exhibited a positive correlation with the gravity of the haemodynamic load, as determined by changes in left ventricular fractional shortening. 4. The results suggest that VOL induces an increase in the expression of lymphocyte beta2-adrenoceptor-specific GRK and beta-arrestin 2 in association with an attenuation in beta2-adrenoceptor levels. It can be speculated that the cardiac circulatory system adapts itself to altered haemodynamic functional demands partly by altering beta2-adrenoceptor signalling.
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PMID:Characterization of lymphocyte beta 2-adrenoceptor signalling in patients with left ventricular volume overload disease. 1190 80

Gprotein-coupled receptor kinases (GRKs) are known to be involved in the development of cardiac hypertrophy. Their exact role and subcellular distribution during cardiac hypertrophy and failure remain to be elucidated. We examined expression and subcellular distribution of GRK2 and GRK5 in the left ventricle of female spontaneously hypertensive heart failure (SHHF) rats at 6 months of age using Western blots and fluorescent confocal microscopy. GRK2 was expressed mainly in the Triton X-100 soluble fraction in the left ventricle with similar expression levels between SHHF and age-matched Wistar-Kyoto (WKY) rats. GRK2 had a striated pattern which colocalized with sarcomeric alpha-actinin and G protein in both SHHF and WKY rat myocytes and specifically accumulated in the intercalated disks of myocytes from SHHF but not WKY rats. GRK5 was expressed in both the Triton X-100 soluble fraction and Triton X-100 insoluble fraction in the left ventricle with similar expression levels between SHHF and WKY rats. GRK5 distributed diffusely in the cytoplasm in both SHHF and WKY rat myocytes and specifically accumulated in the nucleus of myocytes from SHHF but not WKY rats. GRK5 colocalized with coilin, the major component of the nuclear substructure involved in RNA synthesis and processing. The results suggest different roles for GRK2 and GRK5 in G-protein signaling and RNA biogenesis. Subcellular redistribution of GRK2 and GRK5 may be involved in cardiac hypertrophy resulting from chronic hypertension.
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PMID:Myocyte redistribution of GRK2 and GRK5 in hypertensive, heart-failure-prone rats. 1205 42

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

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

Beta-adrenergic receptor (betaAR) blockade is a standard therapy for cardiac failure and ischemia. G protein-coupled receptor kinases (GRKs) desensitize betaARs, suggesting that genetic GRK variants might modify outcomes in these syndromes. Re-sequencing of GRK2 and GRK5 revealed a nonsynonymous polymorphism of GRK5, common in African Americans, in which leucine is substituted for glutamine at position 41. GRK5-Leu41 uncoupled isoproterenol-stimulated responses more effectively than did GRK5-Gln41 in transfected cells and transgenic mice, and, like pharmacological betaAR blockade, GRK5-Leu41 protected against experimental catecholamine-induced cardiomyopathy. Human association studies showed a pharmacogenomic interaction between GRK5-Leu41 and beta-blocker treatment, in which the presence of the GRK5-Leu41 polymorphism was associated with decreased mortality in African Americans with heart failure or cardiac ischemia. In 375 prospectively followed African-American subjects with heart failure, GRK5-Leu41 protected against death or cardiac transplantation. Enhanced betaAR desensitization of excessive catecholamine signaling by GRK5-Leu41 provides a 'genetic beta-blockade' that improves survival in African Americans with heart failure, suggesting a reason for conflicting results of beta-blocker clinical trials in this population.
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PMID:A GRK5 polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure. 1885 42

G protein-coupled receptor (GPCR) kinases (GRKs) are critical regulators of cellular signaling and function. In cardiomyocytes, GRK2 and GRK5 are two GRKs important for myocardial regulation, and both have been shown to be up-regulated in the dysfunctional heart. We report that increased levels and activity of GRK5 in failing myocardium may have unique significance due to its nuclear localization, a property not shared by GRK2. We find that transgenic mice with elevated cardiac GRK5 levels have exaggerated hypertrophy and early heart failure compared with control mice after pressure overload. This pathology is not present in cardiac GRK2-overexpressing mice or in mice with overexpression of a mutant GRK5 that is excluded from the nucleus. Nuclear accumulation of GRK5 is enhanced in myocytes after aortic banding in vivo and in vitro in myocytes after increased G alpha q activity, the trigger for pressure-overload hypertrophy. GRK5 enhances activation of MEF2 in concert with Gq signals, demonstrating that nuclear localized GRK5 regulates gene transcription via a pathway critically linked to myocardial hypertrophy. Mechanistically, we show that this is due to GRK5 acting, in a non-GPCR manner, as a class II histone deacetylase (HDAC) kinase because it can associate with and phosphorylate the myocyte enhancer factor-2 repressor, HDAC5. Moreover, significant HDAC activity can be found with GRK5 in the heart. Our data show that GRK5 is a nuclear HDAC kinase that plays a key role in maladaptive cardiac hypertrophy apparently independent of any action directly on GPCRs.
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PMID:Uncovering G protein-coupled receptor kinase-5 as a histone deacetylase kinase in the nucleus of cardiomyocytes. 1871 Nov 43


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