46 results found
Biressi S, Ma Q, Fukuda N, et al., 2022, Editorial: Methods and applications in striated muscle physiology, FRONTIERS IN PHYSIOLOGY, Vol: 13
Tranter MH, Redfors B, Wright PT, et al., 2022, Hyperthermia as a trigger for Takotsubo syndrome in a rat model, Frontiers in Cardiovascular Medicine, Vol: 9, Pages: 1-9
Takotsubo syndrome is a well-characterized cause of acute yet reversible heart failure associated with periods of intense emotional stress, often mimicking on presentation an acute coronary syndrome. Animal models of Takotsubo syndrome have been developed, either through the application of a stressor, or administration of exogenous catecholamine. We found that in a model of isoproterenol-induced Takotsubo syndrome in anesthetized rats hyperthermia (40–41°C) would occur after the administration of isoproterenol. Maintenance of this hyperthermia would result in an apical hypocontractility typical of the syndrome, whereas prevention of hyperthermia with active cooling to maintain a euthermic core body temperature prevented (but did not subsequently reverse) apical hypocontractility. In vitro experimentation with isolated cardiomyocytes showed no effect of hyperthermia on either baseline contractility or contractility change after beta-adrenoceptor stimulation. We suggest that the rise in body temperature that is characteristic of catecholamine storm may be a component in the development of Takotsubo syndrome.
Couch LS, Fiedler J, Chick G, et al., 2022, Circulating microRNAs predispose to takotsubo syndrome following high-dose adrenaline exposure, Cardiovascular Research, Vol: 118, Pages: 1758-1770, ISSN: 0008-6363
AIMS: Takotsubo syndrome (TTS) is an acute heart failure, typically triggered by high adrenaline during physical or emotional stress. It is distinguished from myocardial infarction (MI) by a characteristic pattern of ventricular basal hypercontractility with hypokinesis of apical segments, and absence of coronary occlusion. We aimed to understand whether recently discovered circulating biomarkers miR-16 and miR-26a, which differentiate TTS from MI at presentation, were mechanistically involved in the pathophysiology of TTS. METHODS AND RESULTS: miR-16 and miR-26a were co-overexpressed in rats with AAV and TTS induced with an adrenaline bolus. Untreated isolated rat cardiomyocytes were transfected with pre-/anti-miRs and functionally assessed. Ventricular basal hypercontraction and apical depression were accentuated in miR-transfected animals after induction of TTS. In vitro miR-16 and/or miR-26a overexpression in isolated apical (but not basal) cardiomyocytes produced strong depression of contraction, with loss of adrenaline sensitivity. They also enhanced the initial positive inotropic effect of adrenaline in basal cells. Decreased contractility after TTS-miRs was reproduced in non-failing human apical cardiomyocytes. Bioinformatic profiling of miR targets, followed by expression assays and functional experiments, identified reductions of CACNB1 (L-type calcium channel Cavβ subunit), RGS4 (regulator of G-protein signalling 4) and G-protein subunit Gβ (GNB1) as underlying these effects. CONCLUSION: miR-16 and miR-26a sensitise the heart to TTS-like changes produced by adrenaline. Since these miRs have been associated with anxiety and depression, they could provide a mechanism whereby priming of the heart by previous stress causes an increased likelihood of TTS in the future. TRANSLATIONAL PERSPECTIVE: TTS-associated miRs have the potential to be active players predisposing to TTS. Feasibly, their measurement in recovered TTS patients during subsequent peri
Wright P, Gorelik J, 2022, Junctophillin-2: Coupling Hopes for Cardiac Gene Therapy to Gene Transcription, CIRCULATION RESEARCH, Vol: 130, Pages: 1318-1320, ISSN: 0009-7330
Wright PT, Gorelik J, Harding SE, 2021, Electrophysiological remodeling: cardiac t-tubules and β-adrenoceptors, Cells, Vol: 10, ISSN: 2073-4409
Beta-adrenoceptors (βAR) are often viewed as archetypal G-protein coupled receptors. Over the past fifteen years, investigations in cardiovascular biology have provided remarkable insights into this receptor family. These studies have shifted pharmacological dogma, from one which centralized the receptor to a new focus on structural micro-domains such as caveolae and t-tubules. Important studies have examined, separately, the structural compartmentation of ion channels and βAR. Despite links being assumed, relatively few studies have specifically examined the direct link between structural remodeling and electrical remodeling with a focus on βAR. In this review, we will examine the nature of receptor and ion channel dysfunction on a substrate of cardiomyocyte microdomain remodeling, as well as the likely ramifications for cardiac electrophysiology. We will then discuss the advances in methodologies in this area with a specific focus on super-resolution microscopy, fluorescent imaging, and new approaches involving microdomain specific, polymer-based agonists. The advent of powerful computational modelling approaches has allowed the science to shift from purely empirical work, and may allow future investigations based on prediction. Issues such as the cross-reactivity of receptors and cellular heterogeneity will also be discussed. Finally, we will speculate as to the potential developments within this field over the next ten years.
Wright P, Tsui S, Francis A, et al., 2020, Approaches to high-throughput analysis of cardiomyocyte contractility, Frontiers in Physiology, Vol: 11, ISSN: 1664-042X
The measurement of the contractile behavior of single cardiomyocytes has made a significant contribution to our understanding of the physiologyand pathophysiology of the myocardium. However, the isolation of cardiomyocytes introducesvarious technical and statistical issues. Traditional video and fluorescence microscopy techniques based around conventional microscopy systems result in low throughput experimental studies, in which single cells are studied over the course of a pharmacologicalor physiologicalintervention. We describe a new approach to these experiments made possible with a new piece of instrumentation, the CytoCypher High-Throughput System (CC-19HTS).Wecan assess the shortening of sarcomeres, cell length, Ca2+handling and cellular morphology of almost 4 cells perminute. Thisincrease in productivity means that batch-to-batch variation can be identified as a major source of variability. The speed of acquisition means that sufficientnumbers of cells in each preparation can be assessed for multiple conditions reducingthese batch effects. We demonstrate the different temporal scales over which the CC-HTS can acquire data. We use statistical analysis methods thatcompensate for the hierarchical effects of clustering withinheart preparations anddemonstrate asignificant false positive rate which is potentially present in conventional studies. We demonstrate a more stringent way toperform these tests. The baseline morphological and functional characteristics of rat, mouse, guinea pig and human cells are explored. Finally, we show data from concentration response experiments revealing the usefulnessof the CC-HTSin suchstudies. We specifically focus on the effects of agents thatdirectly or indirectly affect the activity of the motor proteins involved in the production of cardiomyocyte contraction. A variety of myocardial preparations with differing levels of complexity are in use (e.g. isolated muscl
Schobesberger S, Wright PT, Poulet C, et al., 2020, beta(3)-Adrenoceptor redistribution impairs NO/cGMP/PDE2 signalling in failing cardiomyocytes, eLife, Vol: 9, Pages: 1-15, ISSN: 2050-084X
Cardiomyocyte β3-adrenoceptors (β3-ARs) coupled to soluble guanylyl cyclase (sGC)-dependent production of the second messenger 3’,5’-cyclic guanosine monophosphate (cGMP) have been shown to protect from heart failure. However, the exact localization of these receptors to fine membrane structures and subcellular compartmentation of β3-AR/cGMP signals underpinning this protection in health and disease remain elusive. Here, we used a Förster Resonance Energy Transfer (FRET)-based cGMP biosensor combined with scanning ion conductance microscopy (SICM) to show that functional β3-ARs are mostly confined to the T-tubules of healthy rat cardiomyocytes. Heart failure, induced via myocardial infarction, causes a decrease of the cGMP levels generated by these receptors and a change of subcellular cGMP compartmentation. Furthermore, attenuated cGMP signals led to impaired phosphodiesterase two dependent negative cGMP-to-cAMP cross-talk. In conclusion, topographic and functional reorganization of the β3-AR/cGMP signalosome happens in heart failure and should be considered when designing new therapies acting via this receptor.
Judina A, Gorelik J, Wright PT, 2020, Studying signal compartmentation in adult cardiomyocytes., Biochemical Society Transactions, Vol: 48, Pages: 61-70, ISSN: 0300-5127
Multiple intra-cellular signalling pathways rely on calcium and 3'-5' cyclic adenosine monophosphate (cAMP) to act as secondary messengers. This is especially true in cardiomyocytes which act as the force-producing units of the cardiac muscle and are required to react rapidly to environmental stimuli. The specificity of functional responses within cardiomyocytes and other cell types is produced by the organellar compartmentation of both calcium and cAMP. In this review, we assess the role of molecular localisation and relative contribution of active and passive processes in producing compartmentation. Active processes comprise the creation and destruction of signals, whereas passive processes comprise the release or sequestration of signals. Cardiomyocytes display a highly articulated membrane structure which displays significant cell-to-cell variability. Special attention is paid to the way in which cell membrane caveolae and the transverse-axial tubule system allow molecular localisation. We explore the effects of cell maturation, pathology and regional differences in the organisation of these processes. The subject of signal compartmentation has had a significant amount of attention within the cardiovascular field and has undergone a revolution over the past two decades. Advances in the area have been driven by molecular imaging using fluorescent dyes and genetically encoded constructs based upon fluorescent proteins. We also explore the use of scanning probe microscopy in the area. These techniques allow the analysis of molecular compartmentation within specific organellar compartments which gives researchers an entirely new perspective.
Swiatlowska P, Sanchez-Alonso JL, Wright PT, et al., 2020, Microtubules regulate cardiomyocyte transversal Young's modulus., Proceedings of the National Academy of Sciences of USA, Vol: 117, Pages: 2764-2766, ISSN: 0027-8424
The field of cardiomyocyte mechanobiology is gaining significant attention, due to accumulating evidence concerning the significant role of cellular mechanical effects on the integrated function of the heart. To date, the protein titin has been demonstrated as a major contributor to the cardiomyocytes Young's modulus (YM). The microtubular network represents another potential regulator of cardiac mechanics. However, the contribution of microtubules (MTs) to the membrane YM is still understudied and has not been interrogated in the context of myocardial infarction (MI) or mechanical loading and unloading. Using nanoscale mechanoscanning ion conductance microscopy, we demonstrate that MTs contribute to cardiomyocyte transverse YM in healthy and pathological states with different mechanical loading. Specifically, we show that posttranslational modifications of MTs have differing effects on cardiomyocyte YM: Acetylation provides flexibility, whereas detyrosination imparts rigidity. Further studies demonstrate that there is no correlation between the total protein amount of acetylated and detyrosinated MT. Yet, in the polymerized-only populations, an increased level of acetylation results in a decline of detyrosinated MTs in an MI model.
Swiatlowska PP, Sanchez-Alonso J, Wright P, et al., 2019, Single cell mechanics in failing heart: role of microtubules and mitochondria re-arrangement, ESC, Publisher: WILEY, Pages: 316-316, ISSN: 1388-9842
Wright PT, Sanchez-Alonso JL, Lucarelli C, et al., 2018, Partial mechanical unloading of the heart disrupts L-type calcium channel and beta-adrenoceptor signaling microdomains, Frontiers in Physiology, Vol: 9, ISSN: 1664-042X
Introduction: We investigated the effect of partial mechanical unloading (PMU) of the heart on the physiology of calcium and beta-adrenoceptor-cAMP (βAR-cAMP) microdomains. Previous studies have investigated PMU using a model of heterotopic-heart and lung transplantation (HTHAL). These studies have demonstrated that PMU disrupts the structure of cardiomyocytes and calcium handling. We sought to understand these processes by studying L-Type Calcium Channel (LTCC) activity and sub-type-specific βAR-cAMP signaling within cardiomyocyte membrane microdomains.Method: We utilized an 8-week model of HTHAL, whereby the hearts of syngeneic Lewis rats were transplanted into the abdomens of randomly assigned cage mates. A pronounced atrophy was observed in hearts after HTHAL. Cardiomyocytes were isolated via enzymatic perfusion. We utilized Förster Resonance Energy Transfer (FRET) based cAMP-biosensors and scanning ion conductance microscopy (SICM) based methodologies to study localization of LTCC and βAR-cAMP signaling.Results: β2AR-cAMP responses measured by FRET in the cardiomyocyte cytosol were reduced by PMU (loaded 28.51 ± 7.18% vs. unloaded 10.84 ± 3.27% N,n 4/10-13 mean ± SEM ∗p < 0.05). There was no effect of PMU on β2AR-cAMP signaling in RII_Protein Kinase A domains. β1AR-cAMP was unaffected by PMU in either microdomain. Consistent with this SICM/FRET analysis demonstrated that β2AR-cAMP was specifically reduced in t-tubules (TTs) after PMU (loaded TT 0.721 ± 0.106% vs. loaded crest 0.104 ± 0.062%, unloaded TT 0.112 ± 0.072% vs. unloaded crest 0.219 ± 0.084% N,n 5/6-9 mean ± SEM ∗∗p < 0.01, ∗∗∗p < 0.001 vs. loaded TT). By comparison β1AR-cAMP responses in either TT or sarcolemmal crests were unaffected by the PMU. LTCC occurrence and open probability (Po) were reduced by PMU (loaded TT Po 0.073 ± 0.011% vs. load
Bastug-Özel Z, Wright PT, Kraft AE, et al., 2018, Heart failure leads to altered b2-adrenoceptor/cyclic adenosine monophosphate dynamics in the sarcolemmal phospholemman/Na,KATPase microdomain, Cardiovascular Research, Vol: 115, Pages: 546-555, ISSN: 1755-3245
Aims: Cyclic adenosine monophosphate (cAMP) regulates cardiac excitation-contraction coupling by acting in microdomains associated with sarcolemmal ion channels. However, local real time cAMP dynamics in such microdomains has not been visualized before. We sought to directly monitor cAMP in a microdomain formed around sodium-potassium ATPase (NKA) in healthy and failing cardiomyocytes and to better understand alterations of cAMP compartmentation in heart failure. Methods and Results: A novel Förster resonance energy transfer (FRET)-based biosensor termed PLM-Epac1 was developed by fusing a highly sensitive cAMP sensor Epac1-camps to the C-terminus of phospholemman (PLM). Live cell imaging in PLM-Epac1 and Epac1-camps expressing adult rat ventricular myocytes revealed extensive regulation of NKA/PLM microdomain associated cAMP levels by β2-adrenoceptors (β2-ARs). Local cAMP pools stimulated by these receptors were tightly controlled by phosphodiesterase (PDE) type 3. In chronic heart failure following myocardial infarction, dramatic reduction of the microdomain-specific β2-AR/cAMP signals and β2-AR dependent PLM phosphorylation was accompanied by a pronounced loss of local PDE3 and an increase in PDE2 effects. Conclusions: NKA/PLM complex forms a distinct cAMP microdomain which is directly regulated by β2-ARs and is under predominant control by PDE3. In heart failure, local changes in PDE repertoire result in blunted β2-AR signaling to cAMP in the vicinity of PLM.
Wright P, Lucarelli C, Sanchez-Alonso J, et al., 2018, Mechanical Unloading Suppresses Localized Beta-2 Adrenoceptor and L-type Calcium Channel Function in Healthy and Failing Cardiomyocytes, Circulation 136(Suppl_1.18365):14 Nov 2017
Wright PT, Bhogal N, Diakonov I, et al., 2018, Cardiomyocyte membrane structure and cAMP compartmentation produce anatomical variation in β2AR-cAMP responsiveness in murine hearts, Cell Reports, Vol: 23, Pages: 459-469, ISSN: 2211-1247
Cardiomyocytes from the apex but not the base of the heart increase their contractility in response to β2-adrenoceptor (β2AR) stimulation, which may underlie the development of Takotsubo cardiomyopathy. However, both cell types produce comparable cytosolic amounts of the second messenger cAMP. We investigated this discrepancy using nanoscale imaging techniques and found that, structurally, basal cardiomyocytes have more organized membranes (higher T-tubular and caveolar densities). Local membrane microdomain responses measured in isolated basal cardiomyocytes or in whole hearts revealed significantly smaller and more short-lived β2AR/cAMP signals. Inhibition of PDE4, caveolar disruption by removing cholesterol or genetic deletion of Cav3 eliminated differences in local cAMP production and equilibrated the contractile response to β2AR. We conclude that basal cells possess tighter control of cAMP because of a higher degree of signaling microdomain organization. This provides varying levels of nanostructural control for cAMP-mediated functional effects that orchestrate macroscopic, regional physiological differences within the heart.
Wright PT, Lucarelli C, Sanchez-Alonso J, et al., 2017, Mechanical Unloading Suppresses Localized Beta-2 Adrenoceptor and L-type Calcium Channel Function in Healthy and Failing Cardiomyocytes, Scientific Sessions of the American-Heart-Association / Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Schobesberger S, Wright P, Poulet C, et al., 2017, beta(3) adrenergic signaling alters compartmentation and NO/cGMP/PDE2 signaling in heart failure, Publisher: ELSEVIER SCI LTD, Pages: 36-37, ISSN: 0022-2828
Swiatlowska P, Sanchez-Alonso J, Wright P, et al., 2017, Studying cell membrane nanomechanics in normal and failing hearts - New approach, Publisher: ELSEVIER SCI LTD, Pages: 8-8, ISSN: 0022-2828
Schobesberger S, Wright P, Tokar S, et al., 2017, T-tubule remodelling disturbs localised β2-adrenergic signalling in rat ventricular myocyte during the progression of heart failure, Cardiovascular Research, Vol: 113, Pages: 770-782, ISSN: 0008-6363
AimsCardiomyocyte β2-adrenergic receptor (β2AR) cyclic adenosine monophosphate (cAMP) signalling is regulated by the receptors’ subcellular location within transverse tubules (T-tubules), via interaction with structural and regulatory proteins, which form a signalosome. In chronic heart failure (HF), β2ARs redistribute from T-tubules to the cell surface, which disrupts functional signalosomes and leads to diffuse cAMP signalling. However, the functional consequences of structural changes upon β2AR-cAMP signalling during progression from hypertrophy to advanced HF are unknown.Methods and resultsRat left ventricular myocytes were isolated at 4-, 8-, and 16-week post-myocardial infarction (MI), β2ARs were stimulated either via whole-cell perfusion or locally through the nanopipette of the scanning ion conductance microscope. cAMP release was measured via a Förster Resonance Energy Transfer-based sensor Epac2-camps. Confocal imaging of di-8-ANNEPS-stained cells and immunoblotting were used to determine structural alterations. At 4-week post-MI, T-tubule regularity, density and junctophilin-2 (JPH2) expression were significantly decreased. The amplitude of local β2AR-mediated cAMP in T-tubules was reduced and cAMP diffused throughout the cytosol instead of being locally confined. This was accompanied by partial caveolin-3 (Cav-3) dissociation from the membrane. At 8-week post-MI, the β2AR-mediated cAMP response was observed at the T-tubules and the sarcolemma (crest). Finally, at 16-week post-MI, the whole cell β2AR-mediated cAMP signal was depressed due to adenylate cyclase dysfunction, while overall Cav-3 levels were significantly increased and a substantial portion of Cav-3 dissociated into the cytosol. Overexpression of JPH2 in failing cells in vitro or AAV9.SERCA2a gene therapy in vivo did not improve β2AR-mediated signal compartmentation or reduce cAMP diffusion.ConclusionAlthough changes in T-tubule structure
Surdo NC, Berrera M, Koschinski A, et al., 2017, FRET biosensor uncovers cAMP nano-domains at beta-adrenergic targets that dictate precise tuning of cardiac contractility, Nature Communications, Vol: 8, ISSN: 2041-1723
Compartmentalized cAMP/PKA signalling is now recognized as important for physiology and pathophysiology, yet a detailed understanding of the properties, regulation and function of local cAMP/PKA signals is lacking. Here we present a fluorescence resonance energy transfer (FRET)-based sensor, CUTie, which detects compartmentalized cAMP with unprecedented accuracy. CUTie, targeted to specific multiprotein complexes at discrete plasmalemmal, sarcoplasmic reticular and myofilament sites, reveals differential kinetics and amplitudes of localized cAMP signals. This nanoscopic heterogeneity of cAMP signals is necessary to optimize cardiac contractility upon adrenergic activation. At low adrenergic levels, and those mimicking heart failure, differential local cAMP responses are exacerbated, with near abolition of cAMP signalling at certain locations. This work provides tools and fundamental mechanistic insights into subcellular adrenergic signalling in normal and pathological cardiac function.
Miragoli M, Sanchez Alonso JL, Bhargava A, et al., 2015, Microtubule-dependent mitochondria alignment regulates calcium release in response to nanomechanical stimulus in heart myocytes, Cell Reports, Vol: 14, Pages: 140-151, ISSN: 2211-1247
Arrhythmogenesis during heart failure is a major clinical problem. Regional electrical gradients produce arrhythmias, and cellular ionic transmembrane gradients are its originators. We investigated whether the nanoscale mechanosensitive properties of cardiomyocytes from failing hearts have a bearing upon the initiation of abnormal electrical activity. Hydrojets through a nanopipette indent specific locations on the sarcolemma and initiate intracellular calcium release in both healthy and heart failure cardiomyocytes, as well as in human failing cardiomyocytes. In healthy cells, calcium is locally confined, whereas in failing cardiomyocytes, calcium propagates. Heart failure progressively stiffens the membrane and displaces sub-sarcolemmal mitochondria. Colchicine in healthy cells mimics the failing condition by stiffening the cells, disrupting microtubules, shifting mitochondria, and causing calcium release. Uncoupling the mitochondrial proton gradient abolished calcium initiation in both failing and colchicine-treated cells. We propose the disruption of microtubule-dependent mitochondrial mechanosensor microdomains as a mechanism for abnormal calcium release in failing heart.
Derda AA, O'Gara P, Tranter MH, et al., 2015, Characterization of cardiac stress (Takotsubo syndrome)-related miRNAs ex vivo, Congress of the European-Society-of-Cardiology (ESC), Publisher: OXFORD UNIV PRESS, Pages: 1208-1209, ISSN: 0195-668X
Wright PT, Gorelik J, Schobesberger S, 2015, Studying GPCR/cAMP pharmacologyfrom the perspective of cellularstructure, Frontiers in Pharmacology, Vol: 6, ISSN: 1663-9812
Signal transduction via G-protein coupled receptors (GPCRs) relies upon the productionof cAMP and other signaling cascades. A given receptor and agonist pair, producemultiple effects upon cellular physiology which can be opposite in different cell types.The production of variable cellular effects via the signaling of the same GPCR in differentcell types is a result of signal organization in space and time (compartmentation).This organization is usually based upon the physical and chemical properties of themembranes in which the GPCRs reside and the repertoire of downstream effectors andco-factors that are available at that location. In this review we explore mechanisms ofGPCR signal compartmentation and broadly review the state-of-the-art methodologieswhich can be utilized to study them. We provide a clear rationale for a “localized”approach to the study of the pharmacology and physiology of GPCRs and particularlythe secondary messenger cAMP.
Tranter MH, Wright PT, Harding SE, et al., 2015, Development of therapeutic and preventative strategies for takotsubo syndrome, EUROPEAN JOURNAL OF HEART FAILURE, Vol: 17, Pages: 30-30, ISSN: 1388-9842
Wright PT, Tranter MH, Morley-Smith A, et al., 2015, Is High-Dose Catecholamine Administration in Small Animals an Appropriate Model for Takotsubo Syndrome? - Reply -, CIRCULATION JOURNAL, Vol: 79, Pages: 898-899, ISSN: 1346-9843
Tranter MH, Wright PT, Lyon AR, et al., 2014, Ovariectomy increases epinephrine-induced mortality in a rat takotsubo cardiomyopathy model: the effects of estrogen supplementation, CARDIOVASCULAR RESEARCH, Vol: 103, ISSN: 0008-6363
Wright PT, Tranter MH, Morley-Smith AC, et al., 2014, Pathophysiology of Takotsubo Syndrome - Temporal Phases of Cardiovascular Responses to Extreme Stress, Circulation Journal, Vol: 78, Pages: 1550-1558, ISSN: 1347-4820
Takotsubo syndrome (TTS), also known as takotsubo cardiomyopathy, is an acute heart failure syndrome thattypically occurs after a period of great emotional stress. The archetypal patient is a postmenopausal woman whopresents with chest pain, ST-segment elevation and acute hypokinesia of the apical and middle segment of the leftventricle that extends beyond the territory of a single coronary artery, coupled with hyperkinesia of the basal myocardium.Recent preclinical and clinical studies have shown the importance of high catecholamine levels in precipitatingTTS. We propose that this is caused by activation of β-adrenoceptors and the subsequent activation of anegatively-inotropic pathway, perhaps to protect the heart from catecholamine overload. We explore the pathophysiologyof TTS according to its “phases”, both preclinically and clinically. This will show that the condition is notone of static apical hypokinesia that simply improves, but rather a dynamic condition that changes as the diseaseprogresses. We hope that further exploration of TTS using its “phases” will aid in its characterization, diagnosis andtreatment.
Wright PT, Nikolaev VO, O'Hara T, et al., 2014, Caveolin-3 regulates compartmentation of cardiomyocyte beta2-adrenergic receptor-mediated cAMP signaling, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, Vol: 67, Pages: 38-48, ISSN: 0022-2828
O'Hara T, Wright PT, Nikolaev VO, et al., 2013, Caveolin-3 Restores Local cAMP Signaling Without Restoring T-Tubules in Response to ss 2 Adrenergic Receptor Stimulation in Heart Failure, Scientific Sessions and Resuscitation Science Symposium of the American-Heart-Association, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Schobesberger S, Tokar S, Bhargava A, et al., 2013, Alteration in b2-ARs Dependent cAMP Signalling Linked to Post Infarction Remodelling of T-tubules in Rat Cardiomyocytes, Scientific Sessions and Resuscitation Science Symposium of the American-Heart-Association, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
Gorelik J, Wright PT, Lyon AR, et al., 2013, Spatial control of the beta AR system in heart failure: the transverse tubule and beyond, CARDIOVASCULAR RESEARCH, Vol: 98, Pages: 216-224, ISSN: 0008-6363
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