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Sarcoplasmic reticulum load

Marcela K Preininger, Rajneesh Jha, Joshua T Maxwell, Qingling Wu, Monalisa Singh, Bo Wang, Aarti Dalal, Zachary T Mceachin, Wilfried Rossoll, Chadwick M Hales, Peter S Fischbach, Mary B Wagner, Chunhui Xu
Although β-blockers can be used to eliminate stress-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), this treatment is unsuccessful in ∼25% of cases. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from these patients have potential for use in investigating the phenomenon, but it remains unknown whether they can recapitulate patient-specific drug responses to β-blockers. This study assessed whether the inadequacy of β-blocker therapy in an individual can be observed in vitro using patient-derived CPVT iPSC-CMs...
September 1, 2016: Disease Models & Mechanisms
Esma N Okatan, Aysegul Toy Durak, Belma Turan
Myocardial contractility is controlled by intracellular Ca(2+) cycling with the contribution of sarcoplasmic reticulum (SR). In this study, we aimed to investigate the role of altered SR function in defective regulation of intracellular Ca(2+) levels in rats with metabolic syndrome (MetS) induced by a 16-week high-sucrose drinking-water diet. Electric-field stimulated transient intracellular Ca(2+) changes in MetS cardiomyocytes exhibited significantly reduced amplitude (∼30%) and prolonged time courses (2-fold), as well as depressed SR Ca(2+) loading (∼55%) with increased basal Ca(2+) level...
April 12, 2016: Canadian Journal of Physiology and Pharmacology
Yuanzhao L Darcy, Paula L Diaz-Sylvester, Julio A Copello
K201 (JTV-519) may prevent abnormal Ca(2+) leak from the sarcoplasmic reticulum (SR) in the ischemic heart and skeletal muscle (SkM) by stabilizing the ryanodine receptors (RyRs; RyR1 and RyR2, respectively). We tested direct modulation of the SR Ca(2+)-stimulated ATPase (SERCA) and RyRs by K201. In isolated cardiac and SkM SR microsomes, K201 slowed the rate of SR Ca(2+) loading, suggesting potential SERCA block and/or RyR agonism. K201 displayed Ca(2+)-dependent inhibition of SERCA-dependent ATPase activity, which was measured in microsomes incubated with 200, 2, and 0...
August 2016: Molecular Pharmacology
L Hu, J Wang, H Zhu, X Wu, L Zhou, Y Song, S Zhu, M Hao, C Liu, Y Fan, Y Wang, Q Li
As a result of its spatial confinement in cardiomyocytes, neuronal nitric oxide synthase (nNOS) is thought to regulate mitochondrial and sarcoplasmic reticulum (SR) function by maintaining nitroso-redox balance and Ca(2+) cycling. Thus, we hypothesize that ischemic postconditioning (IPostC) protects hearts against ischemic/reperfusion (I/R) injury through an nNOS-mediated pathway. Isolated mouse hearts were subjected to I/R injury in a Langendorff apparatus, H9C2 cells and primary neonatal rat cardiomyocytes were subjected to hypoxia/reoxygenation (H/R) in vitro...
2016: Cell Death & Disease
B Cicero Willis, Sandeep V Pandit, Daniela Ponce-Balbuena, Manuel Zarzoso, Guadalupe Guerrero-Serna, Bijay Limbu, Makarand Deo, Emmanuel Camors, Rafael J Ramirez, Sergey Mironov, Todd J Herron, Héctor H Valdivia, José Jalife
BACKGROUND: In catecholaminergic polymorphic ventricular tachycardia (CPVT), cardiac Purkinje cells (PCs) appear more susceptible to Ca(2+) dysfunction than ventricular myocytes (VMs). The underlying mechanisms remain unknown. Using a CPVT mouse (RyR2(R4496C+/Cx40eGFP)), we tested whether PC intracellular Ca(2+) ([Ca(2+)]i) dysregulation results from a constitutive [Na(+)]i surplus relative to VMs. METHODS AND RESULTS: Simultaneous optical mapping of voltage and [Ca(2+)]i in CPVT hearts showed that spontaneous Ca(2+) release preceded pacing-induced triggered activity at subendocardial PCs...
June 14, 2016: Circulation
Michelle L Asp, Frances V Sjaastad, Jalal K Siddiqui, Jonathan P Davis, Joseph M Metzger
Cardiac gene delivery of parvalbumin (Parv), an EF-hand Ca(2+) buffer, has been studied as a therapeutic strategy for diastolic heart failure, in which slow Ca(2+) reuptake is an important contributor. A limitation of wild-type (WT) Parv is the significant trade-off between faster relaxation and blunted contraction amplitude, occurring because WT-Parv sequesters Ca(2+) too early in the cardiac cycle and prematurely truncates sarcomere shortening in the facilitation of rapid relaxation. We recently demonstrated that an E → Q substitution (ParvE101Q) at amino acid 12 of the EF-hand Ca(2+)/Mg(2+) binding loop disrupts bidentate Ca(2+) binding, reducing Ca(2+) affinity by 99-fold and increasing Mg(2+) affinity twofold...
May 10, 2016: Biophysical Journal
Liang Xiao, Georgina B Gurrola, Jing Zhang, Carmen R Valdivia, Mario SanMartin, Fernando Z Zamudio, Liming Zhang, Lourival D Possani, Héctor H Valdivia
Calcins are a novel family of scorpion peptides that bind with high affinity to ryanodine receptors (RyRs) and increase their activity by inducing subconductance states. Here, we provide a comprehensive analysis of the structure-function relationships of the eight calcins known to date, based on their primary sequence, three-dimensional modeling, and functional effects on skeletal RyRs (RyR1). Primary sequence alignment and evolutionary analysis show high similarity among all calcins (≥78.8% identity). Other common characteristics include an inhibitor cysteine knot (ICK) motif stabilized by three pairs of disulfide bridges and a dipole moment (DM) formed by positively charged residues clustering on one side of the molecule and neutral and negatively charged residues segregating on the opposite side...
May 2016: Journal of General Physiology
Bettina Sommer, Edgar Flores-Soto, Jorge Reyes-García, Verónica Díaz-Hernández, Verónica Carbajal, Luis M Montaño
UNLABELLED: Membrane depolarization of airway smooth muscle (ASM) opens L-type voltage dependent Ca(2+) channels (L-VDCC) allowing Ca(2+) entrance to produce contraction. In Ca(2+) free conditions Na(+) permeates through L-VDCC in excitable and non-excitable cells and this phenomenon is annulled at µM Ca(2+) concentrations. Membrane depolarization also induces activation of Gq proteins and sarcoplasmic reticulum Ca(2+) release. In bovine ASM, KCl induced a transient contraction sensitive to nifedipine in Ca(2+)free medium, indicating an additional mechanism to the SR-Ca(2+) release...
July 5, 2016: European Journal of Pharmacology
Arthur Oliveira Nonato, Vania C Olivon, Vanessa Dela Justina, Camila Z Zanotto, R Clinton Webb, Rita C Tostes, Victor V Lima, Fernanda R Giachini
We hypothesized that SIRS/endotoxemia-associated hyporesponsiveness to vasoconstrictors is mediated by smaller increases in intracellular Ca(2+) levels due to reduced signaling via the STIM/Orai. Male Wistar rats were injected either with saline or bacterial LPS (i.p.; 10 mg/kg), and experiments were performed 24 h later. LPS-injected rats exhibited decreased systolic blood pressure, increased heart rate, neutrophils' migration into the peritoneal cavity, and elevated alanine aminotransferase levels. Additionally, second-order mesenteric arteries from endotoxemic rats displayed hyporeactivity to contractile agents such as phenylephrine and potassium chloride; decreased contractile responses to Ca(2+); reduced contraction during Ca(2+) loading; and smaller intracellular Ca(2+) stores...
June 2016: Inflammation
Javier Vargas-Medrano, Jorge A Sierra-Fonseca, Luis F Plenge-Tellechea
BACKGROUND: 1,2-Dichlorobenzene (1,2-DCB) is a benzene-derived molecule with two Cl atoms that is commonly utilized in the synthesis of pesticides. 1,2-DCB can be absorbed by living creatures and its effects on naturally-occurring enzymatic systems, including the effects on Ca(2+)-ATPases, have been poorly studied. Therefore, we aimed to study the effect of 1,2-DCB on the Ca(2+)-ATPase from sarcoplasmic reticulum (SERCA), a critical regulator of intracellular Ca(2+) concentration. RESULTS: Concentrations of 0...
2016: BMC Biochemistry
Mark Grinshpon, Vladimir E Bondarenko
The β1-adrenergic signaling system is one of the most important protein signaling systems in cardiac cells. It regulates cardiac action potential duration, intracellular Ca(2+) concentration ([Ca(2+)]i) transients, and contraction force. In this paper, a comprehensive experimentally based mathematical model of the β1-adrenergic signaling system for mouse ventricular myocytes is explored to simulate the effects of moderate stimulations of β1-adrenergic receptors (β1-ARs) on the action potential, Ca(2+) and Na(+) dynamics, as well as the effects of inhibition of protein kinase A (PKA) and phosphodiesterase of type 4 (PDE4)...
June 1, 2016: American Journal of Physiology. Cell Physiology
Pierre Bobin, Audrey Varin, Florence Lefebvre, Rodolphe Fischmeister, Grégoire Vandecasteele, Jérôme Leroy
AIMS: A major concern of using phosphodiesterase (PDE) inhibitors in heart failure is their potential to increase mortality by inducing arrhythmias. By diminishing cyclic adenosine monophosphate (cAMP) hydrolysis, they promote protein kinase A (PKA) activity under β-adrenergic receptor (β-AR) stimulation, hence enhancing Ca(2+) cycling and contraction. Yet, cAMP also activates CaMKII via PKA or the exchange protein Epac, but it remains unknown whether these pathways are involved in the pro-arrhythmic effect of PDE inhibitors...
May 1, 2016: Cardiovascular Research
Victoria Stary, Dheeraj Puppala, Marielle Scherrer-Crosbie, Wolfgang H Dillmann, Antonis A Armoundas
Cardiac alternans has been associated with the incidence of ventricular tachyarrhythmias and sudden cardiac death. The aim of this study was to investigate the effect of impaired mitochondrial function in the genesis of cellular alternans and to examine whether modulating the sarcoplasmic reticulum (SR) Ca(2+)ameliorates the level of alternans. Cardiomyocytes isolated from control and doxycyline-induced sarco(endo)plasmic reticulum Ca(2+)-ATPase 2a (SERCA2a)-upregulated mice were loaded with two different Ca(2+)indicators to selectively measure mitochondrial and cytosolic Ca(2+)using a custom-made fluorescence photometry system...
April 15, 2016: Journal of Applied Physiology
Benjamin R Nelson, Catherine A Makarewich, Douglas M Anderson, Benjamin R Winders, Constantine D Troupes, Fenfen Wu, Austin L Reese, John R McAnally, Xiongwen Chen, Ege T Kavalali, Stephen C Cannon, Steven R Houser, Rhonda Bassel-Duby, Eric N Olson
Muscle contraction depends on release of Ca(2+) from the sarcoplasmic reticulum (SR) and reuptake by the Ca(2+)adenosine triphosphatase SERCA. We discovered a putative muscle-specific long noncoding RNA that encodes a peptide of 34 amino acids and that we named dwarf open reading frame (DWORF). DWORF localizes to the SR membrane, where it enhances SERCA activity by displacing the SERCA inhibitors, phospholamban, sarcolipin, and myoregulin. In mice, overexpression of DWORF in cardiomyocytes increases peak Ca(2+) transient amplitude and SR Ca(2+) load while reducing the time constant of cytosolic Ca(2+) decay during each cycle of contraction-relaxation...
January 15, 2016: Science
Cedric Viero, Silke Wegener, Anke Scholz, Sandra Ruppenthal, Qinghai Tian, Wiebke Tabellion, Michael Kreinest, Matthias W Laschke, Lars Kaestner, Peter Lipp
The precise role of hormones binding to Gαq protein-coupled receptors (H-GαqPCRs) in chronic heart diseases remains poorly understood. To address this, we used a model of cultured adult rat ventricular myocytes stimulated with endothelin-1 (ET-1) or phenylephrine (PE) over a period of 8 days in vitro (DIV). Chronically treated cells showed an increased number of arrhythmogenic Ca(2+) transients when electrically paced at 0.5 Hz. While their post-rest behaviour was preserved, from DIV6 onwards the amplitude of caffeine-evoked Ca(2+) transients was increased in hormone-treated cells, suggesting an elevated sarcoplasmic reticulum Ca(2+) load...
January 2016: Cell Calcium
Angelo Giovanni Torrente, Pietro Mesirca, Patricia Neco, Riccardo Rizzetto, Stefan Dubel, Christian Barrere, Martina Sinegger-Brauns, Joerg Striessnig, Sylvain Richard, Joël Nargeot, Ana Maria Gomez, Matteo Elia Mangoni
AIMS: Sino-atrial node (SAN) automaticity is an essential mechanism of heart rate generation that is still not completely understood. Recent studies highlighted the importance of intracellular Ca(2+) ([Ca(2+)]i) dynamics during SAN pacemaker activity. Nevertheless, the functional role of voltage-dependent L-type Ca(2+) channels in controlling SAN [Ca(2+)]i release is largely unexplored. Since Cav1.3 is the predominant L-type Ca(2+) channel isoform in SAN cells, we studied [Ca(2+)]i dynamics in isolated cells and ex vivo SAN preparations explanted from wild-type (WT) and Cav1...
March 1, 2016: Cardiovascular Research
Haifei Zhang, Mark B Cannell, Shang Jin Kim, Judy J Watson, Ruth Norman, Sarah C Calaghan, Clive H Orchard, Andrew F James
Atrial remodeling due to elevated arterial pressure predisposes the heart to atrial fibrillation (AF). Although abnormal sarcoplasmic reticulum (SR) function has been associated with AF, there is little information on the effects of elevated afterload on atrial Ca2+-handling. We investigated the effects of ascending aortic banding (AoB) on Ca2+-handling in rat isolated atrial myocytes in comparison to age-matched sham-operated animals (Sham). Myocytes were either labelled for ryanodine receptor (RyR) or loaded with fluo-3-AM and imaged by confocal microscopy...
2015: PloS One
Xiyuan Lu, Jennifer Q Kwong, Jeffery D Molkentin, Donald M Bers
RATIONALE: Mitochondria produce ATP, especially critical for survival of highly aerobic cells, such as cardiac myocytes. Conversely, opening of mitochondrial high-conductance and long-lasting permeability transition pores (mPTP) causes respiratory uncoupling, mitochondrial injury, and cell death. However, low conductance and transient mPTP openings (tPTP) might limit mitochondrial Ca(2+) load and be cardioprotective, but direct evidence for tPTP in cells is limited. OBJECTIVE: To directly characterize tPTP occurrence during sarcoplasmic reticulum Ca(2+) release in adult cardiac myocytes...
March 4, 2016: Circulation Research
Michel De Pauw, Kanigula Mubagwa, Dominique Hodeige, Marcel Borgers, Willem Flameng, Johan Van de Voorde, Guy R Heyndrickx
AIM: Rapid pacing (RP) is a regularly used model to induce heart failure in dogs. The aim of the study was to evaluate Ca(2+) handling, left ventricular (LV) contractile response during Ca(2+) administration compared to exercise, as well as oxygen consumption and mechanical efficiency after 48 hours (hrs) of RP. METHODS: 53 mongrel dogs were instrumented to measure LV pressure, LV fractional shortening, regional wall thickening and coronary blood flow. Contractile reserve was measured with isoproterenol and intravenous (IV) Ca(2+) administration...
November 12, 2015: Acta Physiologica
Thomas H Fischer, Jonas Herting, Jörg Eiringhaus, Steffen Pabel, Nico H Hartmann, David Ellenberger, Martin Friedrich, André Renner, Jan Gummert, Lars S Maier, Markus Zabel, Gerd Hasenfuss, Samuel Sossalla
AIMS: Clinical studies have shown differences in the propensity for malignant ventricular arrhythmias between women and men suffering from cardiomyopathies and heart failure (HF). This is clinically relevant as it impacts therapies like prophylactic implantable cardioverter-defibrillator implantation but the pathomechanisms are unknown. As an increased sarcoplasmic reticulum (SR) Ca(2+) leak is arrhythmogenic, it could represent a cellular basis for this paradox. METHODS/RESULTS: We evaluated the SR Ca(2+) leak with respect to sex differences in (i) afterload-induced cardiac hypertrophy (Hy) with preserved left ventricular (LV) function and (ii) end-stage HF...
September 2016: Europace: European Pacing, Arrhythmias, and Cardiac Electrophysiology
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