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Impaired Adrenergic/Protein Kinase A Response of Slow Delayed Rectifier Potassium Channels as a Long QT Syndrome Motif: Importance and Unknowns.
Policarová, M, Novotný, T, Bébarová, M
The Canadian journal of cardiology. 2019;(4):511-522
Abstract
The slow delayed rectifier potassium current (IKs) significantly contributes to cardiac repolarization under specific conditions, particularly at stimulation by the protein kinase A (PKA) during increased sympathetic tone. Impaired PKA-mediated stimulation of IKs channels may considerably aggravate dysfunction of the channels induced by mutations in the KCNQ1 gene that encodes the structure of the α-subunit of IKs channels. These mutations are associated with several subtypes of inherited arrhythmias, mainly long QT syndrome type 1, less commonly short QT syndrome type 2, and atrial fibrillation. The impaired PKA reactivity of IKs channels may significantly increase the risk of arrhythmia in these patients. Unfortunately, only approximately 2.7% of the KCNQ1 variants identified as putatively clinically significant have been studied with respect to this problem. This review summarizes the current knowledge in the field to stress the importance of the PKA-mediated regulation of IKs channels, and to appeal for further analysis of this regulation in KCNQ1 mutations associated with inherited arrhythmogenic syndromes. On the basis of the facts summarized in our review, we suggest several new regions of the α-subunit of the IKs channels as potential contributors to PKA stimulation, namely the S4 and S5 segments, and the S2-S3 and S4-S5 linkers. Deeper knowledge of mechanisms of the impaired PKA response in mutated IKs channels may help to better understand this regulation, and may improve risk stratification and management of patients suffering from related pathologies.
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Ca2+-dependent calcineurin/NFAT signaling in β-adrenergic-induced cardiac hypertrophy.
Khalilimeybodi, A, Daneshmehr, A, Sharif Kashani, B
General physiology and biophysics. 2018;(1):41-56
Abstract
Ca2+ is an important mediator in the β-adrenergic-induced cardiac hypertrophy. The β-adrenergic stimulation alters the Ca2+ transient characteristics including its oscillation frequency, diastolic and systolic levels which lead to the CaN activation and subsequent NFAT-dependent hypertrophic genes transcription. Moreover, β-adrenergic-induced alterations in PKA and GSK3β kinase activities in both the cytosol and the nucleus regulate NFAT nuclear translocation and contribute in its hypertrophic response. Due to the complex nature of CaN/NFAT signaling in cardiac cells, we use a computational approach to investigate the β-adrenergic-induced CaN/NFAT activation in the cardiac myocytes. The presented model predicts well the main physiological characteristics of CaN/NFAT signaling in accordance with the experimental observations. The presented model establishes the previous experimental and mathematical results on the principal role of Ca2+ oscillation frequency in the CaN/NFAT signaling and shows that increase in Ca2+ oscillation frequency enhances CaN activity and its sensitivity to low ISO concentrations. The model illustrates that in addition to the known ISO effect on Ca2+ transient amplitude, ISO-induced alterations in Ca2+ oscillation frequency, PKA and GSK3β kinase activities also greatly affect the β-adrenergic-induced NFAT activity. We also found that PKA has both pro-hypertrophic and anti-hypertrophic effects on NFAT activation and is the main kinase in ISO-induced NFAT activation.
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Chronic β2 -adrenoceptor agonist treatment alters muscle proteome and functional adaptations induced by high intensity training in young men.
Hostrup, M, Onslev, J, Jacobson, GA, Wilson, R, Bangsbo, J
The Journal of physiology. 2018;(2):231-252
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Abstract
KEY POINTS While several studies have investigated the effects of exercise training in human skeletal muscle and the chronic effect of β2 -agonist treatment in rodent muscle, their effects on muscle proteome signature with related functional measures in humans are still incompletely understood. Herein we show that daily β2 -agonist treatment attenuates training-induced enhancements in exercise performance and maximal oxygen consumption, and alters muscle proteome signature and phenotype in trained young men. Daily β2 -agonist treatment abolished several of the training-induced enhancements in muscle oxidative capacity and caused a repression of muscle metabolic pathways; furthermore, β2 -agonist treatment induced a slow-to-fast twitch muscle phenotype transition. The present study indicates that chronic β2 -agonist treatment confounds the positive effect of high intensity training on exercise performance and oxidative capacity, which is of interest for the large proportion of persons using inhaled β2 -agonists on a daily basis, including athletes. ABSTRACT Although the effects of training have been studied for decades, data on muscle proteome signature remodelling induced by high intensity training in relation to functional changes in humans remains incomplete. Likewise, β2 -agonists are frequently used to counteract exercise-induced bronchoconstriction, but the effects β2 -agonist treatment on muscle remodelling and adaptations to training are unknown. In a placebo-controlled parallel study, we randomly assigned 21 trained men to 4 weeks of high intensity training with (HIT+β2 A) or without (HIT) daily inhalation of β2 -agonist (terbutaline, 4 mg dose-1 ). Of 486 proteins identified by mass-spectrometry proteomics of muscle biopsies sampled before and after the intervention, 32 and 85 were changing (false discovery rate (FDR) ≤5%) with the intervention in HIT and HIT+β2 A, respectively. Proteome signature changes were different in HIT and HIT+β2 A (P = 0.005), wherein β2 -agonist caused a repression of 25 proteins in HIT+β2 A compared to HIT, and an upregulation of 7 proteins compared to HIT. β2 -Agonist repressed or even downregulated training-induced enrichment of pathways related to oxidative phosphorylation and glycogen metabolism, but upregulated pathways related to histone trimethylation and the nucleosome. Muscle contractile phenotype changed differently in HIT and HIT+β2 A (P ≤ 0.001), with a fast-to-slow twitch transition in HIT and a slow-to-fast twitch transition in HIT+β2 A. β2 -Agonist attenuated training-induced enhancements in maximal oxygen consumption (P ≤ 0.01) and exercise performance (6.1 vs. 11.6%, P ≤ 0.05) in HIT+β2 A compared to HIT. These findings indicate that daily β2 -agonist treatment attenuates the beneficial effects of high intensity training on exercise performance and oxidative capacity, and causes remodelling of muscle proteome signature towards a fast-twitch phenotype.
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Catecholamine-Dependent β-Adrenergic Signaling in a Pluripotent Stem Cell Model of Takotsubo Cardiomyopathy.
Borchert, T, Hübscher, D, Guessoum, CI, Lam, TD, Ghadri, JR, Schellinger, IN, Tiburcy, M, Liaw, NY, Li, Y, Haas, J, et al
Journal of the American College of Cardiology. 2017;(8):975-991
Abstract
BACKGROUND Takotsubo syndrome (TTS) is characterized by an acute left ventricular dysfunction and is associated with life-threating complications in the acute phase. The underlying disease mechanism in TTS is still unknown. A genetic basis has been suggested to be involved in the pathogenesis. OBJECTIVES The aims of the study were to establish an in vitro induced pluripotent stem cell (iPSC) model of TTS, to test the hypothesis of altered β-adrenergic signaling in TTS iPSC-cardiomyocytes (CMs), and to explore whether genetic susceptibility underlies the pathophysiology of TTS. METHODS Somatic cells of patients with TTS and control subjects were reprogrammed to iPSCs and differentiated into CMs. Three-month-old CMs were subjected to catecholamine stimulation to simulate neurohumoral overstimulation. We investigated β-adrenergic signaling and TTS cardiomyocyte function. RESULTS Enhanced β-adrenergic signaling in TTS-iPSC-CMs under catecholamine-induced stress increased expression of the cardiac stress marker NR4A1; cyclic adenosine monophosphate levels; and cyclic adenosine monophosphate-dependent protein kinase A-mediated hyperphosphorylation of RYR2-S2808, PLN-S16, TNI-S23/24, and Cav1.2-S1928, and leads to a reduced calcium time to transient 50% decay. These cellular catecholamine-dependent responses were mainly mediated by β1-adrenoceptor signaling in TTS. Engineered heart muscles from TTS-iPSC-CMs showed an impaired force of contraction and a higher sensitivity to isoprenaline-stimulated inotropy compared with control subjects. In addition, altered electrical activity and increased lipid accumulation were detected in catecholamine-treated TTS-iPSC-CMs, and were confirmed by differentially expressed lipid transporters CD36 and CPT1C. Furthermore, we uncovered genetic variants in different key regulators of cardiac function. CONCLUSIONS Enhanced β-adrenergic signaling and higher sensitivity to catecholamine-induced toxicity were identified as mechanisms associated with the TTS phenotype. (International Takotsubo Registry [InterTAK Registry] [InterTAK]; NCT01947621).
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A Physiologic Approach to the Pharmacogenomics of Hypertension.
Eadon, MT, Chapman, AB
Advances in chronic kidney disease. 2016;(2):91-105
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Hypertension is a multifactorial condition with diverse physiological systems contributing to its pathogenesis. Individuals exhibit significant variation in their response to antihypertensive agents. Traditional markers, such as age, gender, diet, plasma renin level, and ethnicity, aid in drug selection. However, this review explores the contribution of genetics to facilitate antihypertensive agent selection and predict treatment efficacy. The findings, reproducibility, and limitations of published studies are examined, with emphasis placed on candidate genetic variants affecting drug metabolism, the renin-angiotensin system, adrenergic signalling, and renal sodium reabsorption. Single-nucleotide polymorphisms identified and replicated in unbiased genome-wide association studies of hypertension treatment are reviewed to illustrate the evolving understanding of the disease's complex and polygenic pathophysiology. Implementation efforts at academic centers seek to overcome barriers to the broad adoption of pharmacogenomics in the treatment of hypertension. The level of evidence required to support the implementation of pharmacogenomics in clinical practice is considered.
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β-Adrenergic regulation of the cardiac Na+-K+ ATPase mediated by oxidative signaling.
Galougahi, KK, Liu, CC, Bundgaard, H, Rasmussen, HH
Trends in cardiovascular medicine. 2012;(4):83-7
Abstract
Activation of β-adrenergic receptors (ARs) elicits responses arising from protein kinase A (PKA)-mediated phosphorylation of target proteins that regulate Ca(2+)-dependent excitation-contraction coupling. Some important targets for β-AR- and PKA-dependent pathways, including the sarcolemmal Na(+)-K(+) pump, also undergo oxidative modifications in response to activation of receptor-coupled redox signaling pathways in cardiac myocytes. Here, we highlight how β(1)- and β(3)-AR signaling have opposing effects on functionally important oxidative modification of the Na(+)-K(+) pump molecular complex and how the addition of redox dependence to the canonical phosphorylation dependence of the scheme for β-AR signaling in general expands its versatility but also its complexity. The expanded scheme integrates increased oxidative stress into the pathophysiological effects of adrenergic hyperactivity and provides mechanistic explanation for the efficacy of β-AR blockers in heart failure in which raised intracellular Na(+) levels are detrimental-an explanation not provided by traditionally held views on β-AR-mediated regulation of the pump function.
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Apoptosis in heart failure. -The role of the β-adrenergic receptor-mediated signaling pathway and p53-mediated signaling pathway in the apoptosis of cardiomyocytes-.
Fujita, T, Ishikawa, Y
Circulation journal : official journal of the Japanese Circulation Society. 2011;(8):1811-8
Abstract
The heart works as a driving force to deliver oxygen and nutrients to the whole body. Interrupting this function for only several minutes can cause critical and permanent damage to the human body. Thus, heart failure (HF) or attenuated cardiac function is an important factor that affects both patient's the quality of life and longevity. Numerous clinical and basic studies have been performed to clarify the complex pathophysiology of HF and to develop effective therapies. Modulating the β-adrenergic receptor-mediated signaling pathway has been one of the most crucial targets for HF therapy. Impressively, recent reports identified p53, a well-known tumor suppressor, as a major player in the development of HF. The present review highlights the apoptosis of cardiomyocytes, which is one of the important mechanisms that leads to HF and can be induced by both β-adrenergic signaling and p53. Consideration of the cross-talk among these major pathways will be important when developing effective and safe therapies for HF.
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Inhibition of superoxide generation and myeloperoxidase release by carvedilol after receptor and nonreceptor stimulation of human neutrophils.
Macickova, T, Pecivova, J, Nosal, R, Lojek, A, Pekarova, M, Cupanikova, D
Neuro endocrinology letters. 2008;(5):790-3
Abstract
OBJECTIVES To compare three stimuli which activate human neutrophils with different signal transduction mechanisms, in order to better localize the effect of the beta-adrenoceptor antagonist carvedilol (CARV) on superoxide generation (O2*-) and myeloperoxidase release (MPO). The effect of CARV [0.1-100 micromol/l] on O2*- generation and MPO release from isolated human neutrophils was studied after specific receptor activator N-formyl-methionyl-leucyl-phenylalanine (fMLP) and nonreceptor phorbol-12-myristate-13-acetate (PMA) and calcium ionophor (A23187) stimuli. METHODS O2*- generation was measured as superoxide dismutase inhibitable reduction of cytochrome c and MPO release as the oxidation of o-dianisidine in the presence of hydrogen peroxide in a spectrophotometer Hewlet Packard 8452 A at respective 550 and 463 nm. RESULTS CARV had no effect on O2*- generation and MPO release in nonstimulated cells. In the concentration 10 and 100 micromol/l, it significantly decreased fMLP and PMA stimulated O2*- generation and MPO release. Incubation of neutrophils with CARV [100 micromol/l] caused significant inhibition of O2*- generation and MPO release induced by A23187. Wortmannin, a specific inhibitor of 1-phosphatidylinositol-3-kinase, inhibited significantly only fMLP stimulated O2*- generation. CARV [100 micromol/l] with wortmannin [50 nmol/l] further decreased O2*- generation after the same stimulus. CONCLUSION CARV decreased O2*- generation and MPO release from isolated human neutrophils both by membrane-operating stimulus - fMLP and membrane bypassing activators - PMA and A 23187. This fact, together with effect the of wortmannin, indicates that the inhibition may be attributed to the non-specific action of CARV and its interference with phospholipase D signaling pathway, which plays only a minor role in proteinkinase C stimulated O2*- generation.
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Variants of the peroxisome proliferator-activated receptor gamma- and beta-adrenergic receptor genes are associated with measures of compensatory eating behaviors in young children.
Cecil, JE, Palmer, CN, Fischer, B, Watt, P, Wallis, DJ, Murrie, I, Hetherington, MM
The American journal of clinical nutrition. 2007;(1):167-73
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Abstract
BACKGROUND Young children can regulate energy precisely in the short term, showing the potential for an innate compensation mechanism of eating behavior. However, data suggest that precise compensation is attenuated as a function of increasing adiposity, parental feeding style, and age. Common variation in candidate obesity genes may account for some of the individual variation observed in short-term energy compensation. Polymorphisms in the peroxisome proliferator-activated receptor gamma (PPARG) and beta-adrenergic receptor (ADRB3) genes have been linked to increased body mass index (BMI; in kg/m(2)), obesity, and more recently dietary nutrients and preferences. In addition, common variation in ADRB3 interacts with PPARG to modulate adult body weight. OBJECTIVE This study investigated whether variants in these genes were associated with measurable effects on child eating behavior. DESIGN Children (n=84) aged 4-10 y were prospectively selected for variants of the PPARG locus (Pro12Ala, C1431T). Heights and weights were measured. Energy intake from a test meal was measured 90 min after ingestion of a no-energy (NE), low-energy (LE), or high-energy (HE) preload, and the compensation index (COMPX) was calculated. RESULTS BMI differed significantly by gene model, whereby Pro12Ala was associated with a lower BMI. Poor COMPX was associated with the PPARG T1431 allele (P=0.009). There was a significant interaction between COMPX and the ADRB3 Trp64Arg variant in modulating compensation (P=0.003), whereas the Arg64 allele was associated with good compensation (P=0.001). CONCLUSIONS This is the first study to suggest that a genetic interaction involving ADRB3 and PPARG variants influences eating behavior in children.
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Structure-function of alpha1-adrenergic receptors.
Perez, DM
Biochemical pharmacology. 2007;(8):1051-62
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The Easson-Stedman hypothesis provided the rationale for the first studies of drug design for the alpha(1)-adrenergic receptor. Through chemical modifications of the catecholamine core structure, the need was established for a protonated amine, a beta-hydroxyl on a chiral center, and an aromatic ring with substitutions capable of hydrogen bonding. After the receptors were cloned and three alpha(1)-adrenergic receptor subtypes were discovered, drug design became focused on the analysis of receptor structure and new interactions were uncovered. It became clear that alpha(1)- and beta-adrenergic receptors did not share stringent homology in the ligand-binding pocket but this difference has allowed for more selective drug design. Novel discoveries on allosterism and agonist trafficking may be used in the future design of therapeutics with fewer side effects. This review will explore past and current knowledge of the structure-function of the alpha(1)-adrenergic receptor subtypes.