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Lunde I.G.,University of Oslo | Aronsen J.M.,University of Oslo | Aronsen J.M.,Bjorknes College | Kvaloy H.,University of Oslo | And 6 more authors.
Physiological Genomics | Year: 2012

Reversible protein O-GlcNAc modification has emerged as an essential intracellular signaling system in several tissues, including cardiovascular pathophysiology related to diabetes and acute ischemic stress. We tested the hypothesis that cardiac O-GlcNAc signaling is altered in chronic cardiac hypertrophy and failure of different etiologies. Global protein O-GlcNAcylation and the main enzymes regulating O-GlcNAc, O-GlcNAc transferase (OGT), O-GlcNAcase (OGA), and glutamine-fructose-6-phosphate amidotransferase (GFAT) were measured by immunoblot and/or real-time RT-PCR analyses of left ventricular tissue from aortic stenosis (AS) patients and rat models of hypertension, myocardial infarction (MI), and aortic banding (AB), with and without failure. We show here that global O-GlcNAcylation was increased by 65% in AS patients, by 47% in hypertensive rats, by 81 and 58% post-AB, and 37 and 60% post-MI in hypertrophic and failing hearts, respectively (P < 0.05). Noticeably, protein O-GlcNAcylation patterns varied in hypertrophic vs. failing hearts, and the most extensive O-GlcNAcylation was observed on proteins of 20-100 kDa in size. OGT, OGA, and GFAT2 protein and/or mRNA levels were increased by pressure overload, while neither was regulated by myocardial infarction. Pharmacological inhibition of OGA decreased cardiac contractility in post-MI failing hearts, demonstrating a possible role of O-GlcNAcylation in development of chronic cardiac dysfunction. Our data support the novel concept that O-GlcNAc signaling is altered in various etiologies of cardiac hypertrophy and failure, including human aortic stenosis. This not only provides an exciting basis for discovery of new mechanisms underlying pathological cardiac remodeling but also implies protein O-GlcNAcylation as a possible new therapeutic target in heart failure. © 2012 the American Physiological Society.

Espe E.K.S.,University of Oslo | Aronsen J.M.,University of Oslo | Aronsen J.M.,Bjorknes College | Skrbic B.,University of Oslo | And 5 more authors.
Magnetic Resonance in Medicine | Year: 2013

Phase-contrast MRI (PC-MRI) velocimetry is a noninvasive, high-resolution motion assessment tool. However, high motion sensitivity requires strong motion-encoding magnetic gradients, making phase-contrast-MRI prone to baseline shift artifacts due to the generation of eddy currents. In this study, we propose a novel nine-point balanced velocity-encoding strategy, designed to be more accurate in the presence of strong and rapidly changing gradients. The proposed method was validated using a rotating phantom, and its robustness and precision were explored and compared with established approaches through computer simulations and in vivo experiments. Computer simulations yielded a 39-57% improvement in velocity-noise ratio (corresponding to a 27-33% reduction in measurement error), depending on which method was used for comparison. Moreover, in vivo experiments confirmed this by demonstrating a 26-53% reduction in accumulated velocity error over the R-R interval. The nine-point balanced phase-contrast-MRI-encoding strategy is likely useful for settings where high spatial and temporal resolution and/or high motion sensitivity is required, such as in high-resolution rodent myocardial tissue phase mapping. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc. Copyright © 2012 Wiley Periodicals, Inc.

Gjerdalen G.F.,University of Oslo | Gjerdalen G.F.,Bjorknes College | Hisdal J.,University of Oslo | Hisdal J.,Bjorknes College | And 4 more authors.
Scandinavian Journal of Medicine and Science in Sports | Year: 2014

This investigation explores the cardiac four-chamber remodeling response to training in male players in Norwegian professional football league, and ethnicity as determinants in the development of athlete's heart. Standard 2D echocardiographic examination and analysis of all four cavities were performed in 504 football players of Caucasian origin, 49 of African origin, and 47 matched Caucasian controls (<3h training /week). All results were indexed to body surface area (BSA). Most athletes exhibited BSA-indexed values within normal ranges. Left ventricle (LV) mass was equally enlarged in both groups of athletes, but LV relative wall thickness and right ventricular (RV) relative wall thickness were increased in Africans compared with Caucasian athletes (0.37±0.06 vs 0.33±0.06 and 0.25±0.06 vs 0.22±0.04, respectively). Both LV and RV were smaller in Africans than in Caucasian athletes (67.8±12.0ml/m2 vs 73.6±13.2ml/m2 and 12.8±2.1 vs 13.7±2.4cm2/m2, respectively, both P<0.05), while left and right atria increased similarly. This first large-scale echocardiographic survey of elite football players in a Scandinavian league suggests use of BSA-indexed upper normal limits for both LV and RV in athletes. African athletes had significantly more concentric remodeled LV and RV than the Caucasian athletes. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Espe E.K.,University of Oslo | Aronsen J.M.,University of Oslo | Aronsen J.M.,Bjorknes College | Skardal K.,University of Oslo | And 3 more authors.
Journal of Cardiovascular Magnetic Resonance | Year: 2013

Background: Phase contrast velocimetry cardiovascular magnetic resonance (PC-CMR) is a powerful and versatile tool allowing assessment of in vivo motion of the myocardium. However, PC-CMR is sensitive to motion related artifacts causing errors that are geometrically systematic, rendering regional analysis of myocardial function challenging. The objective of this study was to establish an optimized PC-CMR method able to provide novel insight in the complex regional motion and strain of the rodent myocardium, and provide a proof-of-concept in normal and diseased rat hearts with higher temporal and spatial resolution than previously reported. Methods. A PC-CMR protocol optimized for assessing the motion and deformation of the myocardium in rats with high spatiotemporal resolution was established, and ten animals with different degree of cardiac dysfunction underwent examination and served as proof-of-concept. Global and regional myocardial velocities and circumferential strain were calculated, and the results were compared to five control animals. Furthermore, the global strain measurements were validated against speckle-tracking echocardiography, and inter- and intrastudy variability of the protocol were evaluated. Results: The presented method allows assessment of regional myocardial function in rats with high level of detail; temporal resolution was 3.2 ms, and analysis was done using 32 circumferential segments. In the dysfunctional hearts, global and regional function were distinctly altered, including reduced global peak values, increased regional heterogeneity and increased index of dyssynchrony. Strain derived from the PC-CMR data was in excellent agreement with echocardiography (r = 0.95, p < 0.001; limits-of-agreement -0.02 ± 3.92%strain), and intra- and interstudy variability were low for both velocity and strain (limits-of-agreement, radial motion: 0.01 ± 0.32 cm/s and -0.06 ± 0.75 cm/s; circumferential strain: -0.16 ± 0.89%strain and -0.71 ± 1.67%strain, for intra- and interstudy, respectively). Conclusion: We demonstrate, for the first time, that PC-CMR enables high-resolution evaluation of in vivo circumferential strain in addition to myocardial motion of the rat heart. In combination with the superior geometric robustness of CMR, this ultimately provides a tool for longitudinal studies of regional function in rodents with high level of detail. © 2013 Espe et al.; licensee BioMed Central Ltd.

Aronsen J.M.,University of Oslo | Aronsen J.M.,Bjorknes College | Swift F.,University of Oslo | Sejersted O.M.,University of Oslo
Journal of Molecular and Cellular Cardiology | Year: 2013

The excitation-contraction coupling (EC-coupling) links membrane depolarization with contraction in cardiomyocytes. Ca2+ induced opening of ryanodine receptors (RyRs) leads to Ca2+ induced Ca2+ release (CICR) from the sarcoplasmic reticulum (SR) into the dyadic cleft between the t-tubules and SR. Ca2+ is removed from the cytosol by the SR Ca2+ ATPase (SERCA2) and the Na,Ca-exchanger (NCX). The NCX connects cardiac Ca2+ and Na+-transport, leading to Na+-dependent regulation of EC-coupling by several mechanisms of which some still lack firm experimental evidence. Firstly, NCX might contribute to CICR during an action potential (AP) as Na+-accumulation at the intracellular site together with depolarization will trigger reverse mode exchange bringing Ca2+ into the dyadic cleft. The controversial issue is the nature of the compartment in which Na+ accumulates. It seems not to be the bulk cytosol, but is it part of a widespread subsarcolemmal space, a localized microdomain ("fuzzy space"), or as we propose, a more localized "spot" to which only a few membrane proteins have shared access (nanodomains)? Also, there seems to be spots where the Na,K-pump (NKA) will cause local Na+ depletion. Secondly, Na+ determines the rate of cytosolic Ca2+ removal and SR Ca2+ load by regulating the SERCA2/NCX-balance during the decay of the Ca2+ transient. The aim of this review is to describe available data and current concepts of Na+-mediated regulation of cardiac EC-coupling, with special focus on subcellular microdomains and the potential roles of Na+ transport proteins in regulating CICR and Ca2+ extrusion in cardiomyocytes. We propose that voltage gated Na+ channels, NCX and the NKA α2-isoform all regulate cardiac EC-coupling through control of the "Na+ concentration in specific subcellular nanodomains in cardiomyocytes. This article is part of a Special Issue entitled "Na+ Regulation in Cardiac Myocytes.". © 2013 Elsevier Ltd.

Aronsen J.M.,University of Oslo | Aronsen J.M.,Bjorknes College | Skogestad J.,University of Oslo | Lewalle A.,King's College London | And 8 more authors.
Journal of Physiology | Year: 2015

Key points: Hypokalaemia is a risk factor for development of ventricular arrhythmias. In rat ventricular myocytes, low extracellular K+ (corresponding to clinical moderate hypokalaemia) increased Ca2+ wave probability, Ca2+ transient amplitude, sarcoplasmic reticulum (SR) Ca2+ load and induced SR Ca2+ leak. Low extracellular K+ reduced Na+,K+-ATPase (NKA) activity and hyperpolarized the resting membrane potential in ventricular myocytes. Both experimental data and modelling indicate that reduced NKA activity and subsequent Na+ accumulation sensed by the Na+, Ca2+ exchanger (NCX) lead to increased Ca2+ transient amplitude despite concomitant hyperpolarization of the resting membrane potential. Low extracellular K+ induced Ca2+ overload by lowering NKA α2 activity. Triggered ventricular arrhythmias in patients with hypokalaemia may therefore be attributed to reduced NCX forward mode activity linked to an effect on the NKA α2 isoform. Hypokalaemia is a risk factor for development of ventricular arrhythmias. The aim of this study was to determine the cellular mechanisms leading to triggering of arrhythmias in ventricular myocytes exposed to low Ko. Low Ko, corresponding to moderate hypokalaemia, increased Ca2+ transient amplitude, sarcoplasmic reticulum (SR) Ca2+ load, SR Ca2+ leak and Ca2+ wave probability in field stimulated rat ventricular myocytes. The mechanisms leading to Ca2+ overload were examined. Low Ko reduced Na+,K+-ATPase (NKA) currents, increased cytosolic Na+ concentration and increased the Na+ level sensed by the Na+, Ca2+ exchanger (NCX). Low Ko also hyperpolarized the resting membrane potential (RMP) without significant alterations in action potential duration. Experiments in voltage clamped and field stimulated ventricular myocytes, along with mathematical modelling, suggested that low Ko increases the Ca2+ transient amplitude by reducing NKA activity despite hyperpolarization of the RMP. Selective inhibition of the NKA α2 isoform by low dose ouabain abolished the ability of low Ko to reduce NKA currents, to increase Na+ levels sensed by NCX and to increase the Ca2+ transient amplitude. We conclude that low Ko, within the range of moderate hypokalaemia, increases Ca2+ levels in ventricular myocytes by reducing the pumping rate of the NKA α2 isoform with subsequent Na+ accumulation sensed by the NCX. These data highlight reduced NKA α2-mediated control of NCX activity as a possible mechanism underlying triggered ventricular arrhythmias in patients with hypokalaemia. © 2014 The Physiological Society.

Hussain R.I.,University of Oslo | Aronsen J.M.,University of Oslo | Aronsen J.M.,Bjorknes College | Afzal F.,University of Oslo | And 6 more authors.
Journal of Molecular and Cellular Cardiology | Year: 2013

Beta-adrenergic receptor (βAR) inotropic effects are attenuated and muscarinic receptor-mediated inhibition thereof is enhanced in heart failure. We investigated if increased Gi activity contributes to attenuated βAR-inotropic effects and potentiates muscarinic accentuated antagonism in failing rat ventricle. Contractility was measured in ventricular strips and adenylyl cyclase (AC) activity in ventricular membranes from rats with post-infarction heart failure (HF) or Sham-operated controls (Sham). The maximal βAR-mediated inotropic effect of isoproterenol was reduced by ~70% and basal, βAR- & forskolin-stimulated AC activity was significantly lower in HF vs. Sham. Carbachol-evoked antagonism of the βAR-mediated inotropic response was complete only in HF despite a ~40% reduction in the ability of carbachol to inhibit βAR-stimulated AC. However, neither the relative efficacy (contractility decreased by ~46%) nor the potency of carbachol to inhibit the βAR inotropic response differed between Sham and HF ventricle. Pertussis toxin (PTX) inactivation of Gi did not increase the maximal βAR inotropic effect or the attenuated basal, βAR- & forskolin-stimulated AC activity in HF, but increased the potency of isoproterenol only in Sham (~0.5 log unit). In HF ventricle pretreated with PTX, simultaneous inhibition of phosphodiesterases 3,4 (PDE3,4) alone produced a larger inotropic response than isoproterenol in ventricle untreated with PTX (84% and 48% above basal respectively). In the absence of PTX, PDE3,4 inhibition evoked negligible inotropic effects in HF. These data are not consistent with the hypothesis that increased Gi activity contributes to the reduced βAR-mediated inotropic response and AC activity in failing ventricle. The data, however, support the hypothesis that Gi, through chronic receptor independent inhibition of AC, together with PDE3,4 activity, is necessary to maintain a low basal level of contractility. © 2012 Elsevier Ltd.

PubMed | Domain for Mental and Physical Health, Bjorknes College, University of Oslo and Norwegian Institute of Public Health
Type: | Journal: Environment international | Year: 2016

Polychlorinated dibenzo-p-dioxins/dibenzofurans (dioxins) and polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) with potentially adverse impact on child neurodevelopment. Whether the potential detrimental effects of dioxins and PCBs on neurodevelopment are of specific or unspecific character is not clear.The purpose of the current study was to examine the influence of maternal dietary exposure to dioxins and PCBs on ADHD symptoms and cognitive functioning in preschoolers. We aimed to investigate a range of functions, in particular IQ, expressive language, and executive functions.This study includes n=1024 children enrolled in a longitudinal prospective study of ADHD (the ADHD Study), with participants recruited from The Norwegian Mother and Child Cohort Study (MoBa). Boys and girls aged 3.5years participated in extensive clinical assessments using well-validated tools; The Preschool Age Psychiatric Assessment interview (PAPA), Stanford-Binet 5th revision (SB-5), Child Development Inventory (CDI), and Behavior Rating Inventory of Executive Function, Preschool version (BRIEF-P). Maternal dietary exposure to dioxins and PCBs was estimated based on a validated food frequency questionnaire (FFQ) answered mid-pregnancy and a database of dioxin and PCB concentrations in Norwegian foods. Exposure to dioxins and dioxin-like PCBs (dl-compounds) was expressed in total toxic equivalents (TEQ), and PCB-153 was used as marker for non-dioxin-like PCBs (ndl-PCBs). Generalized linear and additive models adjusted for confounders were used to examine exposure-outcome associations.Exposure to PCB-153 or dl-compound was not significantly associated with any of the outcome measures when analyses were performed for boys and girls together. After stratifying by sex, adjusted analyses indicated a small inverse association with language in girls. An increase in the exposure variables of 1 SD was associated with a reduction in language score of -0.2 [CI -0.4, -0.1] for PCB-153 and -0.2 [CI -0.5, -0.1] for dl-compounds in girls. For boys, exposure to PCB-153 or dl-compounds was not associated with language skills. The difference between sex-specific associations was not statistically significant (p-value=0.13). No sex-specific effects were observed for ADHD-symptoms, IQ scores, or executive functions.We found no indications that variation in current low-level exposure to PCB-153 or dl-compounds in Norway is associated with variation ADHD-symptoms, verbal/non-verbal IQ, or executive functions including working memory in preschoolers. However, our findings indicated that maternal dietary exposure to PCB-153 or dl-compounds during pregnancy was significantly associated with poorer expressive language skills in preschool girls, although the sex-specific associations were not significantly different.

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