Publications
302 results found
Dias P, Navaratnarajah M, Alayoubi S, et al., 2014, Ivabradine Reduces α-Smooth Muscle Actin Expression, Proliferation and Collagen Production in Human Cardiac Fibroblasts, Publisher: Elsevier, Pages: 759a-759a
Gandhi A, Siedlecka U, Shah AP, et al., 2013, The Effect of SN-6, a Novel Sodium-Calcium Exchange Inhibitor, on Contractility and Calcium Handling in Isolated Failing Rat Ventricular Myocytes, CARDIOVASCULAR THERAPEUTICS, Vol: 31, Pages: E115-E124, ISSN: 1755-5914
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- Citations: 12
Zarrinpashneh E, Poggioli T, Sarathchandra P, et al., 2013, Ablation of SGK1 impairs endothelial cell migration and tube formation leading to decreased neo-angiogenesis following myocardial infarction, PLoS ONE, Vol: 8, ISSN: 1932-6203
Serum and glucocorticoid inducible kinase 1 (SGK1) plays a pivotal role in early angiogenesis during embryonic development. In this study, we sought to define the SGK1 downstream signalling pathways in the adult heart and to elucidate their role in cardiac neo-angiogenesis and wound healing after myocardial ischemia. To this end, we employed a viable SGK1 knockout mouse model generated in a 129/SvJ background. Ablation of SGK1 in these mice caused a significant decrease in phosphorylation of SGK1 target protein NDRG1, which correlated with alterations in NF-κB signalling and expression of its downstream target protein, VEGF-A. Disruption of these signalling pathways was accompanied by smaller heart and body size. Moreover, the lack of SGK1 led to defective endothelial cell (ECs) migration and tube formation in vitro, and increased scarring with decreased angiogenesis in vivo after myocardial infarct. This study underscores the importance of SGK1 signalling in cardiac neo-angiogenesis and wound healing after an ischemic insult in vivo.
Terracciano CM, Hancox JC, 2013, ORM-10103: a significant advance in sodium-calcium exchanger pharmacology?, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 170, Pages: 765-767, ISSN: 0007-1188
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- Citations: 4
Dias P, Terracciano CM, 2013, Hyperpolarization-activated cyclic nucleotide-gated channels and ventricular arrhythmias in heart failure: A novel target for therapy?, Journal of the American Heart Association, Vol: 2, ISSN: 2047-9980
Ibrahim M, Terracciano CM, 2013, Reversibility of T-tubule remodelling in heart failure: mechanical load as a dynamic regulator of the T-tubules, CARDIOVASCULAR RESEARCH, Vol: 98, Pages: 225-232, ISSN: 0008-6363
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- Citations: 32
Rao C, Prodromakis T, Kolker L, et al., 2013, The effect of microgrooved culture substrates on calcium cycling of cardiac myocytes derived from human induced pluripotent stem cells, Biomaterials, Vol: 34, Pages: 2399-2411, ISSN: 0142-9612
Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) have been widely proposed as in vitro models of myocardial physiology and disease. A significant obstacle, however, is their immature phenotype. We hypothesised that Ca2+ cycling of iPSC-CM is influenced by culture conditions and can be manipulated to obtain a more mature cellular behaviour. To test this hypothesis we seeded iPSC-CM onto fibronectin coated microgrooved polydimethylsiloxane (PDMS) scaffolds fabricated using photolithography, or onto unstructured PDMS membrane. After two weeks in culture, the structure and function of iPSC-CM were studied. PDMS microgrooved culture substrates brought about cellular alignment (p < 0.0001) and more organised sarcomere. The Ca2+ cycling properties of iPSC-CM cultured on these substrates were significantly altered with a shorter time to peak amplitude (p = 0.0002 at 1 Hz), and more organised sarcoplasmic reticulum (SR) Ca2+ release in response to caffeine (p < 0.0001), suggesting improved SR Ca2+ cycling. These changes were not associated with modifications in gene expression. Whilst structured tissue culture may make iPSC-CM more representative of adult myocardium, further construct development and characterisation is required to optimise iPSC-CM as a model of adult myocardium.
Ibrahim M, Navaratnarajah M, Siedlecka U, et al., 2013, Mechanical unloading reverses transverse tubule remodelling and normalises local calcium-induced calcium release in a rodent model of heart failure, Spring Meeting for Clinician Scientists in Training, Publisher: ELSEVIER SCIENCE INC, Pages: 54-54, ISSN: 0140-6736
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- Citations: 1
Navaratnarajah M, Ibrahim M, Siedlecka U, et al., 2013, Influence of ivabradine on reverse remodelling during mechanical unloading, CARDIOVASCULAR RESEARCH, Vol: 97, Pages: 230-239, ISSN: 0008-6363
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- Citations: 19
Ibrahim M, Navaratnarajah M, Kukadia P, et al., 2013, Heterotopic abdominal heart transplantation in rats for functional studies of ventricular unloading, JOURNAL OF SURGICAL RESEARCH, Vol: 179, Pages: E31-E39, ISSN: 0022-4804
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- Citations: 15
Ibrahim M, Siedlecka U, Buyandelger B, et al., 2013, A critical role for Telethonin in regulating t-tubule structure and function in the mammalian heart, Hum Mol Genet, Vol: 22, Pages: 372-383, ISSN: 1460-2083
The transverse (t)-tubule system plays an essential role in healthy and diseased heart muscle, particularly in Ca(2+)-induced Ca(2+) release (CICR), and its structural disruption is an early event in heart failure. Both mechanical overload and unloading alter t-tubule structure, but the mechanisms mediating the normally tight regulation of the t-tubules in response to load variation are poorly understood. Telethonin (Tcap) is a stretch-sensitive Z-disc protein that binds to proteins in the t-tubule membrane. To assess its role in regulating t-tubule structure and function, we used Tcap knockout (KO) mice and investigated cardiomyocyte t-tubule and cell structure and CICR over time and following mechanical overload. In cardiomyocytes from 3-month-old KO (3mKO), there were isolated t-tubule defects and Ca(2+) transient dysynchrony without whole heart and cellular dysfunction. Ca(2+) spark frequency more than doubled in 3mKO. At 8 months of age (8mKO), cardiomyocytes showed progressive loss of t-tubules and remodelling of the cell surface, with prolonged and dysynchronous Ca(2+) transients. Ca(2+) spark frequency was elevated and the L-type Ca(2+) channel was depressed at 8 months only. After mechanical overload obtained by aortic banding constriction, the Ca(2+) transient was prolonged in both wild type and KO. Mechanical overload increased the Ca(2+) spark frequency in KO alone, where there was also significantly more t-tubule loss, with a greater deterioration in t-tubule regularity. In conjunction, Tcap KO showed severe loss of cell surface ultrastructure. These data suggest that Tcap is a critical, load-sensitive regulator of t-tubule structure and function.
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
Cartledge JE, Tesfom M, Dias P, et al., 2012, Freshly Isolated Fibroblasts From Normal Hearts Affect Cardiomyocyte Structure and Function Via Paracrine Communication, and These Effects are Altered in Fibroblasts From Pressure Overloaded Hearts, CIRCULATION, Vol: 126, ISSN: 0009-7322
Ibrahim M, Rao C, Athanasiou T, et al., 2012, Mechanical unloading and cell therapy have a synergistic role in the recovery and regeneration of the failing heart, EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY, Vol: 42, Pages: 312-318, ISSN: 1010-7940
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- Citations: 17
Ibrahim M, Terracciano C, Yacoub MH, 2012, Can Bridge to Recovery Help to Reveal the Secrets of the Failing Heart?, CURRENT CARDIOLOGY REPORTS, Vol: 14, Pages: 392-396, ISSN: 1523-3782
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- Citations: 8
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.
Martin CA, Siedlecka U, Kemmerich K, et al., 2012, Reduced Na+ and higher K+ channel expression and function contribute to right ventricular origin of arrhythmias in Scn5a+/- mice, Open Biology, Vol: 2, ISSN: 2046-2441
Brugada syndrome (BrS) is associated with ventricular tachycardia originating particularly in the right ventricle (RV). We explore electrophysiological features predisposing to such arrhythmic tendency and their possible RV localization in a heterozygotic Scn5a+/− murine model. Nav1.5 mRNA and protein expression were lower in Scn5a+/− than wild-type (WT), with a further reduction in the RV compared with the left ventricle (LV). RVs showed higher expression levels of Kv4.2, Kv4.3 and KChIP2 in both Scn5a+/− and WT. Action potential upstroke velocity and maximum Na+ current (INa) density were correspondingly decreased in Scn5a+/−, with a further reduction in the RV. The voltage dependence of inactivation was shifted to more negative values in Scn5a+/−. These findings are predictive of a localized depolarization abnormality leading to slowed conduction. Persistent Na+ current (IpNa) density was decreased in a similar pattern to INa. RV transient outward current (Ito) density was greater than LV in both WT and Scn5a+/−, and had larger time constants of inactivation. These findings were also consistent with the observation that AP durations were smallest in the RV of Scn5a+/−, fulfilling predictions of an increased heterogeneity of repolarization as an additional possible electrophysiological mechanism for arrhythmogenesis in BrS.
Martin CA, Siedlecka U, Kemmerich K, et al., 2012, RIGHT VENTRICULAR ORIGIN OF ARRHYTHMIAS IN <i>SCN5A</i>+/- MICE IS DUE TO REDUCED NA plus AND HIGHER K plus CHANNEL EXPRESSION AND FUNCTION, Annual Conference of the British-Cardiovascular-Society (BCS), Publisher: B M J PUBLISHING GROUP, Pages: A2-A3, ISSN: 1355-6037
Cartledge J, Clark LA, Ibrahim M, et al., 2012, Cardiac fibroblasts regulate adult cardiomyocyte calcium handling in co-culture by paracrine signalling mediated by endothelin-1, 2nd Congress of the European-Society-of-Cardiology Council on Basic Cardiovascular Science - Frontiers in Cardiovascular Biology, Publisher: OXFORD UNIV PRESS, Pages: S109-S109, ISSN: 0008-6363
Camelliti P, Dudhia J, Dias P, et al., 2012, Electrophysiological characterisation of the porcine right and left ventricle using myocardial slices, 2nd Congress of the European-Society-of-Cardiology Council on Basic Cardiovascular Science - Frontiers in Cardiovascular Biology, Publisher: OXFORD UNIV PRESS, Pages: S64-S64, ISSN: 0008-6363
Rao C, Prodromakis T, Chaudhry U, et al., 2012, Sarcoplasmic reticulum calcium release in response to caffeine is more organised in cardiomyocytes differentiated from iPSC cultured on structured substrates suggesting a matured phenotype, 2nd Congress of the European-Society-of-Cardiology Council on Basic Cardiovascular Science - Frontiers in Cardiovascular Biology, Publisher: OXFORD UNIV PRESS, Pages: S68-S68, ISSN: 0008-6363
Simrick S, Kreutzer R, Rao C, et al., 2012, Pronounced stress-induced lethality in popdc1/2 null mutants, 2nd Congress of the European-Society-of-Cardiology Council on Basic Cardiovascular Science - Frontiers in Cardiovascular Biology, Publisher: OXFORD UNIV PRESS, Pages: S53-S53, ISSN: 0008-6363
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- Citations: 2
Kukadia P, Ibrahim M, Navaratnarajah M, et al., 2012, T-Tubule Morphology and Local Ca<SUP>2+</SUP>-Induced Ca<SUP>2+</SUP> Release in Rat Ventricular Cardiomyocytes are Sensitive to Chronic Changes in Mechanical Load of the Heart, BIOPHYSICAL JOURNAL, Vol: 102, Pages: 551A-552A, ISSN: 0006-3495
Rao C, Prodromakis T, Chaudhry U, et al., 2012, Structured Culture Scaffolds Improve the Calcium Handling Properties of Cardiomyocytes Differentiated from Induced Pluripotent Stem Cells, BIOPHYSICAL JOURNAL, Vol: 102, Pages: 103A-103A, ISSN: 0006-3495
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- Citations: 1
Navaratnarajah M, van Doorn C, Siedlecka U, et al., 2011, Combined Clenbuterol and Metoprolol Therapy Improves Cardiac Function and Calcium Handling in a Rodent Model of Heart Failure, but Does Not Prevent Myocardial Atrophy or Enhance Myocyte Recovery Associated with Mechanical Unloading, CIRCULATION, Vol: 124, ISSN: 0009-7322
Navaratnarajah M, Ibrahim M, Siedlecka U, et al., 2011, Ivabradine Reduces Interstitial Fibrosis and Enhances the Recovery of Cardiomyocyte Excitation-Contraction Coupling Produced by Mechanical Unloading, CIRCULATION, Vol: 124, ISSN: 0009-7322
Shintani Y, Kapoor A, Drexler H, et al., 2011, A Novel Toll-Like Receptor 9 Signaling in Cardiomyocytes, CIRCULATION, Vol: 124, ISSN: 0009-7322
Siedlecka U, Navaratnarajah M, Gandhi A, et al., 2011, Clenbuterol Affects Cardiomyocyte Contractility Via A β2-Adrenoceptor Independent Pathway, CIRCULATION, Vol: 124, ISSN: 0009-7322
Ibrahim M, Terracciano CM, Yacoub MH, 2011, Bridge to Recovery: What Remains to be Discovered?, CARDIOLOGY CLINICS, Vol: 29, Pages: 531-+, ISSN: 0733-8651
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- Citations: 7
Fernandez-Fuente M, Terracciano CM, Pilsworth R, et al., 2011, Characterisation of sarcoplasmic reticulum calcium release in equine and human myotubes derived from MyoD-transformed fibroblasts, 16th International Congress of the World-Muscle-Society, Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: 695-695, ISSN: 0960-8966
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