Publications
205 results found
Ibrahim M, Kukadia P, Siedlecka U, et al., 2012, Cardiomyocyte Ca2+ handling and structure is regulated by degree and duration of mechanical load variation, Journal of Cellular and Molecular Medicine, Vol: 16, Pages: 2910-2918, ISSN: 1582-4934
Wright PT, Nikolaev VO, Tokar S, et al., 2012, Caveolin3 Depletion Modifies β2AR-cAMP Responses at Both Cellular and Sub-Cellular Levels in Cardiomyocytes, CIRCULATION, Vol: 126, ISSN: 0009-7322
Wright PT, Diakonov I, Nikolaev VO, et al., 2012, Myocardial Gradients in Caveolar Number Modulate Cardiomyocyte Contractile Response to Specific β2AR Stimulation, CIRCULATION, Vol: 126, ISSN: 0009-7322
Bhargava A, O'Hara T, Sikkel MB, et al., 2012, Nanoscale Movement of L-Type Calcium Channels in the Cardiomyocyte Membrane Can Contribute to Arrhythmia During Heart Failure, CIRCULATION, Vol: 126, ISSN: 0009-7322
Paur H, Wright PT, Sikkel MB, et al., 2012, High levels of circulating epinephrine trigger apical cardiodepression in a β2-adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy., Circulation Journal, Vol: 6, Pages: 697-706
Takahashi Y, Shevchuk AI, Novak P, et al., 2012, Topographical and electrochemical nanoscale imaging of living cells using voltage-switching mode scanning electrochemical microscopy, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 109, Pages: 11540-11545, ISSN: 0027-8424
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- Citations: 169
Ibrahim M, Navaratnarajah M, Siedlecka U, et al., 2012, Mechanical unloading reverses transverse tubule remodelling and normalizes local Ca2+-induced Ca2+ release in a rodent model of heart failure, European Journal of Heart Failure, Vol: 14, Pages: 571-580, ISSN: 1879-0844
AimsCa2+-induced Ca2+ release (CICR) is critical for contraction in cardiomyocytes. The transverse (t)-tubule system guarantees the proximity of the triggers for Ca2+ release [L-type Ca2+ channel, dihydropyridine receptors (DHPRs)] and the sarcoplasmic reticulum Ca2+ release channels [ryanodine receptors (RyRs)]. Transverse tubule disruption occurs early in heart failure (HF). Clinical studies of left ventricular assist devices in HF indicate that mechanical unloading induces reverse remodelling. We hypothesize that unloading of failing hearts normalizes t-tubule structure and improves CICR.Methods and resultsHeart failure was induced in Lewis rats by left coronary artery ligation for 12 weeks; sham-operated animals were used as controls. Failing hearts were mechanically unloaded for 4 weeks by heterotopic abdominal heart transplantation (HF-UN). HF reduced the t-tubule density measured by di-8-ANEPPS staining in isolated left ventricular myocytes, and this was reversed by unloading. The deterioration in the regularity of the t-tubule system in HF was also reversed in HF-UN. Scanning ion conductance microscopy showed the reappearance of normal surface striations in HF-UN. Electron microscopy revealed recovery of normal t-tubule microarchitecture in HF-UN. L-type Ca2+ current density, measured using whole-cell patch clamping, was reduced in HF but unaffected by unloading. The variance of the time-to-peak of the Ca2+ transient, an index of CICR dyssynchrony, was increased in HF and normalized by unloading. The increased Ca2+ spark frequency observed in HF was reduced in HF-UN. These results could be explained by the recoupling of orphaned RyRs in HF, as indicated by immunofluorescence.ConclusionsOur data show that mechanical unloading of the failing heart reverses the pathological remodelling of the t-tubule system and improves CICR.
Wright PT, Pannell LMK, Nikolaev VO, et al., 2012, Imaging regional differences in beta-2 adrenergic receptor function at the cellular level, BSCR/BAS Joint Spring Meeting
Potter CMF, Schobesberger S, Lundberg MH, et al., 2012, Correction: Shape and Compliance of Endothelial Cells after Shear Stress In Vitro or from Different Aortic Regions: Scanning Ion Conductance Microscopy Study, PLoS ONE, Vol: 7
Shevchuk AI, Novak P, Taylor M, et al., 2012, An alternative mechanism of clathrin-coated pit closure revealed by ion conductance microscopy, JOURNAL OF CELL BIOLOGY, Vol: 197, Pages: 499-508, ISSN: 0021-9525
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- Citations: 65
Wright PT, Diakonov I, Tokar S, et al., 2012, Beta-2 adrenergic receptor signaling in adult rat ventricular myocytes at 4, 8 and 16 weeks after myocardial infarction, 2nd Congress of the European-Society-of-Cardiology Council on Basic Cardiovascular Science - Frontiers in Cardiovascular Biology, Publisher: OXFORD UNIV PRESS, Pages: S24-S24, ISSN: 0008-6363
Wright PT, Pannell LMK, Lyon AR, et al., 2012, The negatively inotropic effect of adrenaline stress is not completely linked to the reduction of cAMP release mediated by the Gs/Gi switch, 2nd Congress of the European-Society-of-Cardiology Council on Basic Cardiovascular Science - Frontiers in Cardiovascular Biology, Publisher: OXFORD UNIV PRESS, Pages: S18-S18, ISSN: 0008-6363
Tokar S, Schobesberger S, Singh A, et al., 2012, Progressive changes in cardiomyocyte structure and beta-2 adrenergic receptors cAMP signaling localisation in a rat model of myocardial infarction, 2nd Congress of the European-Society-of-Cardiology Council on Basic Cardiovascular Science - Frontiers in Cardiovascular Biology, Publisher: OXFORD UNIV PRESS, Pages: S48-S48, ISSN: 0008-6363
Miragoli M, Lab MJ, Singh A, et al., 2012, The progression towards heart failure exposes the heart to a mechano-arrhythmic response related to the cellular membrane compliance, 2nd Congress of the European-Society-of-Cardiology Council on Basic Cardiovascular Science - Frontiers in Cardiovascular Biology, Publisher: OXFORD UNIV PRESS, Pages: S46-S47, ISSN: 0008-6363
Potter CMF, Schobesberger S, Lundberg MH, et al., 2012, Shape and Compliance of Endothelial Cells after Shear Stress In Vitro or from Different Aortic Regions: Scanning Ion Conductance Microscopy Study, PLOS ONE, Vol: 7, ISSN: 1932-6203
ObjectiveTo measure the elongation and compliance of endothelial cells subjected to different patterns of shear stress in vitro, and to compare these parameters with the elongation and compliance of endothelial cells from different regions of the intact aorta.Materials and MethodsPorcine aortic endothelial cells were cultured for 6 days under static conditions or on an orbital shaker. The shaker generated a wave of medium, inducing pulsatile shear stress with a preferred orientation at the edge of the well or steadier shear stress with changing orientation at its centre. The topography and compliance of these cells and cells from the inner and outer curvature of ex vivo porcine aortic arches were measured by scanning ion conductance microscopy (SICM).ResultsCells cultured under oriented shear stress were more elongated and less compliant than cells grown under static conditions or under shear stress with no preferred orientation. Cells from the outer curvature of the aorta were more elongated and less compliant than cells from the inner curvature.ConclusionThe elongation and compliance of cultured endothelial cells vary according to the pattern of applied shear stress, and are inversely correlated. A similar inverse correlation occurs in the aortic arch, with variation between regions thought to experience different haemodynamic stresses.
Lyon AR, Nikolaev VO, Miragoli M, et al., 2012, Plasticity of surface structures and β(2)-adrenergic receptor localization in failing ventricular cardiomyocytes during recovery from heart failure, Circulation: Heart Failure, Vol: 5, Pages: 357-365
Weber B, Schoenauer R, Papadopulos F, et al., 2011, Engineering of living autologous human umbilical cord cell-based septal occluder membranes using composite PGA-P4HB matrices, BIOMATERIALS, Vol: 32, Pages: 9630-9641, ISSN: 0142-9612
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- Citations: 15
Lyon AR, Nikolaev VO, Miragoli M, et al., 2011, Plasticity of Surface Structures and Beta 2-adrenergic Receptor Localization in Failing Ventricular Cardiomyocytes During Recovery From Heart Failure, CIRCULATION, Vol: 124, ISSN: 0009-7322
Miragoli M, Kadir SHSA, Sheppard MN, et al., 2011, A Protective Antiarrhythmic Role of Ursodeoxycholic Acid in an <i>In Vitro</i> Rat Model of the Cholestatic Fetal Heart, HEPATOLOGY, Vol: 54, Pages: 1282-1292, ISSN: 0270-9139
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- Citations: 63
Ibrahim M, Gorelik J, Yacoub MH, et al., 2011, The structure and function of cardiac t-tubules in health and disease, PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, Vol: 278, Pages: 2714-2723, ISSN: 0962-8452
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- Citations: 97
Shevchuk AI, Novak P, Takahashi Y, et al., 2011, Realizing the biological and biomedical potential of nanoscale imaging using a pipette probe., Nanomedicine (London, England), Vol: 6, Pages: 565-75, ISSN: 1748-6963
Cells naturally operate on the nanoscale level, with molecules combining together to form complex molecular machines, which can work together to enable normal cell function or go wrong as in the case of many diseases. Visualizing these key processes on the nanoscale has been difficult and two main approaches have been used to date; nanometer resolution imaging of fixed cells using electron microscopy, or imaging live cells using optical or fluorescence microscopy, with a resolution of a few hundred nanometers. Scanning probe microscopy has the potential to allow live cells to be imaged at nanoscale resolution and a noncontact method based on the use of a nanopipette probe has been developed over the last 10 years that allows both topographic and functional imaging. The rapid progress in this area of research over the last 4 years is reviewed in this article, which shows that imaging of complex cellular structures and tissues is now possible and that these methods are now sufficiently mature to provide new insights into important diseases.
Ruenraroengsak P, Novak P, Berhanu D, et al., 2011, Respiratory epithelial cytotoxicity and membrane damage (holes) caused by amine-modified nanoparticles., Nanotoxicology, ISSN: 1743-5404
Abstract The respiratory epithelium is a significant target of inhaled, nano-sized particles, the biological reactivity of which will depend on its physicochemical properties. Surface-modified, 50 and 100 nm, polystyrene latex nanoparticles (NPs) were used as model particles to examine the effect of particle size and surface chemistry on transformed human alveolar epithelial type 1-like cells (TT1). Live images of TT1 exposed to amine-modified NPs taken by hopping probe ion conductance microscopy revealed severe damage and holes on cell membranes that were not observed with other types of NPs. This paralleled induction of cell detachment, cytotoxicity and apoptotic (caspase-3/7 and caspase-9) cell death, and increased release of CXCL8 (IL-8). In contrast, unmodified, carboxyl-modified 50 nm NPs and the 100 nm NPs did not cause membrane damage, and were less reactive. Thus, the susceptibility and membrane damage to respiratory epithelium following inhalation of NPs will depend on both surface chemistry (e.g., cationic) and nano-size.
Miragoli M, Moshkov A, Novak P, et al., 2011, Scanning ion conductance microscopy: a convergent high-resolution technology for multi-parametric analysis of living cardiovascular cells, Journal of the Royal Society Interface, Vol: 8, Pages: 913-925, ISSN: 1742-5662
Cardiovascular diseases are complex pathologies that include alterations of various cell functions at the levels of intact tissue, single cells and subcellular signalling compartments. Conventional techniques to study these processes are extremely divergent and rely on a combination of individual methods, which usually provide spatially and temporally limited information on single parameters of interest. This review describes scanning ion conductance microscopy (SICM) as a novel versatile technique capable of simultaneously reporting various structural and functional parameters at nanometre resolution in living cardiovascular cells at the level of the whole tissue, single cells and at the subcellular level, to investigate the mechanisms of cardiovascular disease. SICM is a multimodal imaging technology that allows concurrent and dynamic analysis of membrane morphology and various functional parameters (cell volume, membrane potentials, cellular contraction, single ion-channel currents and some parameters of intracellular signalling) in intact living cardiovascular cells and tissues with nanometre resolution at different levels of organization (tissue, cellular and subcellular levels). Using this technique, we showed that at the tissue level, cell orientation in the inner and outer aortic arch distinguishes atheroprone and atheroprotected regions. At the cellular level, heart failure leads to a pronounced loss of T-tubules in cardiac myocytes accompanied by a reduction in Z-groove ratio. We also demonstrated the capability of SICM to measure the entire cell volume as an index of cellular hypertrophy. This method can be further combined with fluorescence to simultaneously measure cardiomyocyte contraction and intracellular calcium transients or to map subcellular localization of membrane receptors coupled to cyclic adenosine monophosphate production. The SICM pipette can be used for patch-clamp recordings of membrane potential and single channel currents. In conclusio
Földes G, Mioulane M, Wright JS, et al., 2011, Modulation of human embryonic stem cell-derived cardiomyocyte growth: a testbed for studying human cardiac hypertrophy?, Journal of molecular and cellular cardiology, Vol: 50, Pages: 367-76, ISSN: 1095-8584
Human embryonic stem cell-derived cardiomyocytes (hESC-CM) are being developed for tissue repair and as a model system for cardiac physiology and pathophysiology. However, the signaling requirements of their growth have not yet been fully characterized. We showed that hESC-CM retain their capacity for increase in size in long-term culture. Exposing hESC-CM to hypertrophic stimuli such as equiaxial cyclic stretch, angiotensin II, and phenylephrine (PE) increased cell size and volume, percentage of hESC-CM with organized sarcomeres, levels of ANF, and cytoskeletal assembly. PE effects on cell size were separable from those on cell cycle. Changes in cell size by PE were completely inhibited by p38-MAPK, calcineurin/FKBP, and mTOR blockers. p38-MAPK and calcineurin were also implicated in basal cell growth. Inhibitors of ERK, JNK, and CaMK II partially reduced PE effects; PKG or GSK3β inhibitors had no effect. The role of p38-MAPK was confirmed by an additional pharmacological inhibitor and adenoviral infection of hESC-CM with a dominant-inhibitory form of p38-MAPK. Infection of hESC-CM with constitutively active upstream MAP2K3b resulted in an increased cell size, sarcomere and cytoskeletal assembly, elongation of the cells, and induction of ANF mRNA levels. siRNA knockdown of p38-MAPK inhibited PE-induced effects on cell size. These results reveal an important role for active protein kinase signaling in hESC-CM growth and hypertrophy, with potential implications for hESC-CM as a novel in vitro test system. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited".
Potter CMF, Lundberg MH, Harrington LS, et al., 2011, Role of Shear Stress in Endothelial Cell Morphology and Expression of Cyclooxygenase Isoforms, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, Vol: 31, Pages: 384-U314, ISSN: 1079-5642
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- Citations: 62
Williamson C, Miragoli M, Kadir SSA, et al., 2011, Bile Acid Signaling in Fetal Tissues: Implications for Intrahepatic Cholestasis of Pregnancy, DIGESTIVE DISEASES, Vol: 29, Pages: 58-61, ISSN: 0257-2753
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- Citations: 44
Ibrahim M, Navaratnarajah M, Siedlecka U, et al., 2010, Mechanical Unloading Of Failing Hearts Normalises Ca2+-induced Ca2+ Release By Reverse Remodelling Of The T-tubule System, Aswan Heart Science Centre: Science and Practice Series
Ibrahim M, Moshkov AV, Hall AR, et al., 2010, Cytoskeletal Protein 4.1R is Required for Normal Cardiac Myocyte Membrane Structure and Stiffness, CIRCULATION, Vol: 122, ISSN: 0009-7322
Ibrahim M, Al Masri A, Navaratnarajah M, et al., 2010, Prolonged mechanical unloading affects cardiomyocyte excitation-contraction coupling, transverse-tubule structure, and the cell surface, FASEB JOURNAL, Vol: 24, Pages: 3321-3329, ISSN: 0892-6638
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- Citations: 59
Kadir SHSA, Miragoli M, Abu-Hayyeh S, et al., 2010, Bile Acid-Induced Arrhythmia Is Mediated by Muscarinic M-2 Receptors in Neonatal Rat Cardiomyocytes, PLOS ONE, Vol: 5, ISSN: 1932-6203
BackgroundIntrahepatic cholestasis of pregnancy (ICP) is a common disease affecting up to 5% of pregnancies and which can cause fetal arrhythmia and sudden intrauterine death. We previously demonstrated that bile acid taurocholate (TC), which is raised in the bloodstream of ICP, can acutely alter the rate and rhythm of contraction and induce abnormal calcium destabilization in cultured neonatal rat cardiomyocytes (NRCM). Apart from their hepatic functions bile acids are ubiquitous signalling molecules with diverse systemic effects mediated by either the nuclear receptor FXR or by a recently discovered G-protein coupled receptor TGR5. We aim to investigate the mechanism of bile-acid induced arrhythmogenic effects in an in-vitro model of the fetal heart.Methods and ResultsLevels of bile acid transporters and nuclear receptor FXR were studied by quantitative real time PCR, western blot and immunostaining, which showed low levels of expression. We did not observe functional involvement of the canonical receptors FXR and TGR5. Instead, we found that TC binds to the muscarinic M2 receptor in NRCM and serves as a partial agonist of this receptor in terms of inhibitory effect on intracellular cAMP and negative chronotropic response. Pharmacological inhibition and siRNA-knockdown of the M2 receptor completely abolished the negative effect of TC on contraction, calcium transient amplitude and synchronisation in NRCM clusters.ConclusionWe conclude that in NRCM the TC-induced arrhythmia is mediated by the partial agonism at the M2 receptor. This mechanism might serve as a promising new therapeutic target for fetal arrhythmia.
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