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Sarcoplasmic reticulum load

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https://www.readbyqxmd.com/read/29614261/the-novel-camkii-inhibitor-gs-680-reduces-diastolic-sr-ca-leak-and-prevents-camkii-dependent-pro-arrhythmic-activity
#1
S Lebek, A Plößl, M Baier, J Mustroph, D Tarnowski, C M Lücht, S Schopka, B Floerchinger, C Schmid, Y Zausig, N Pagratis, B Marchand, D O Koltun, W K Hung, S Ahmadyar, L Belardinelli, L S Maier, S Wagner
RATIONALE: Ca/calmodulin-dependent protein kinase II (CaMKII) was shown to increase diastolic sarcoplasmic reticulum (SR) Ca leak, which can result in delayed afterdepolarizations and triggered arrhythmias. Since increased CaMKII expression and activity has been mechanistically linked to arrhythmias in human heart failure (HF) and atrial fibrillation (AF), specific strategies aimed at CaMKII inhibition may have therapeutic potential. OBJECTIVE: We tested the antiarrhythmic and inotropic effects of a novel selective and ATP-competitive CaMKII inhibitor (GS-680)...
March 31, 2018: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/29604965/computational-modeling-of-amylin-induced-calcium-dysregulation-in-rat-ventricular-cardiomyocytes
#2
Bradley D Stewart, Caitlin E Scott, Thomas P McCoy, Guo Yin, Florin Despa, Sanda Despa, Peter M Kekenes-Huskey
Hyperamylinemia is a condition that accompanies obesity and precedes type II diabetes, and it is characterized by above-normal blood levels of amylin, the pancreas-derived peptide. Human amylin oligomerizes easily and can deposit in the pancreas [1], brain [2], and heart [3], where they have been associated with calcium dysregulation. In the heart, accumulating evidence suggests that human amylin oligomers form moderately cation-selective [4,5] channels that embed in the cell sarcolemma (SL). The oligomers increase membrane conductance in a concentration-dependent manner [5], which is correlated with elevated cytosolic Ca2+ ...
May 2018: Cell Calcium
https://www.readbyqxmd.com/read/29521549/cardiac-adenovirus-associated-viral-presenilin-1-gene-delivery-protects-the-left-ventricular-function-of-the-heart-via-regulating-ryr2-function-in-post-ischaemic-heart-failure
#3
Tian Li, Yafeng Shen, Li Su, Xiaoyan Fan, Fangxing Lin, Xuting Ye, Dianer Ding, Ying Tang, Yongji Yang, Changhai Lei, Shi Hu
Post-ischaemic heart failure is a major cause of death worldwide. Reperfusion of infarcted heart tissue after myocardial infarction has been an important medical intervention to improve outcomes. However, disturbances in Ca2+ and redox homeostasis at the cellular level caused by ischaemia/reperfusion remain major clinical challenges. In this study, we investigated the potential of adeno-associated virus (AAV)-9-mediated cardiac expression of a Type-2 ryanodine receptor (RyR2) degradation-associated gene, Presenilin 1 (PSEN1), to combat post-ischaemic heart failure...
March 21, 2018: Journal of Drug Targeting
https://www.readbyqxmd.com/read/29500669/the-role-of-ryr2-oxidation-in-the-blunted-frequency-dependent-facilitation-of-ca-2-transient-amplitude-in-rabbit-failing-myocytes
#4
Elisa Bovo, Stefan R Mazurek, Aleksey V Zima
Defective Ca2+ regulation plays a key role in the blunted force-frequency response in heart failure (HF). Since HF is commonly associated with oxidative stress, we studied whether oxidation of ryanodine receptor (RyR2) contributes to this defect. In control ventricular myocytes, oxidative stress induced formation of disulfide bonds between RyR2 subunits: intersubunit cross-linking (XL). Western blot analysis and Ca2+ imaging revealed a strong positive correlation between RyR2 XL and sarcoplasmic reticulum (SR) Ca2+ leak...
March 2, 2018: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/29212769/functional-and-structural-characterization-of-a-novel-malignant-hyperthermia-susceptible-variant-of-dhpr-%C3%AE-1a-subunit-cacnb1
#5
Claudio F Perez, Jose M Eltit, Jose R Lopez, Dóra Bodnár, Angela F Dulhunty, Shouvik Aditya, Marco G Casarotto
Malignant hyperthermia (MH) susceptibility has been recently linked to a novel variant of β1a subunit of the dihydropyridine receptor (DHPR), a channel essential for Ca2+ regulation in skeletal muscle. Here we evaluate the effect of the mutant variant V156A on the structure/function of DHPR β1a subunit and assess its role on Ca2+ metabolism of cultured myotubes. Using differential scanning fluorimetry, we show that mutation V156A causes a significant reduction in thermal stability of the Src homology 3/guanylate kinase core domain of β1a subunit...
March 1, 2018: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/29150445/the-antiapoptotic-protein-hax-1-mediates-half-of-phospholamban-s-inhibitory-activity-on-calcium-cycling-and-contractility-in-the-heart
#6
Philip A Bidwell, Kobra Haghighi, Evangelia G Kranias
The antiapoptotic protein HAX-1 (HS-associated protein X-1) localizes to sarcoplasmic reticulum (SR) in the heart and interacts with the small membrane protein phospholamban (PLN), inhibiting the cardiac sarco/endoplasmic reticulum calcium ATPase 2a (SERCA2a) in the regulation of overall calcium handling and heart muscle contractility. However, because global HAX-1 deletion causes early lethality, how much endogenous HAX-1 contributes to PLN's inhibitory activity on calcium cycling is unknown. We therefore generated a cardiac-specific and inducible knock-out mouse model...
January 5, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29150444/toll-like-receptor-4-induced-ryanodine-receptor-2-oxidation-and-sarcoplasmic-reticulum-ca-2-leakage-promote-cardiac-contractile-dysfunction-in-sepsis
#7
Jie Yang, Rui Zhang, Xin Jiang, Jingzhang Lv, Ying Li, Hongyu Ye, Wenjuan Liu, Gang Wang, Cuicui Zhang, Na Zheng, Ming Dong, Yan Wang, Peiya Chen, Kumar Santosh, Yong Jiang, Jie Liu
Studies suggest the potential role of a sarcoplasmic reticulum (SR) Ca2+ leak in cardiac contractile dysfunction in sepsis. However, direct supporting evidence is lacking, and the mechanisms underlying this SR leak are poorly understood. Here, we investigated the changes in cardiac Ca2+ handling and contraction in LPS-treated rat cardiomyocytes and a mouse model of polymicrobial sepsis produced by cecal ligation and puncture (CLP). LPS decreased the systolic Ca2+ transient and myocyte contraction as well as SR Ca2+ content...
January 19, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29030236/accentuated-vagal-antagonism-paradoxically-increases-ryanodine-receptor-calcium-leak-in-long-term-exercised-calsequestrin2-knockout-mice
#8
Hsiang-Ting Ho, Senthil Thambidorai, Björn C Knollmann, George E Billman, Sandor Györke, Anuradha Kalyanasundaram
BACKGROUND: Long-term aerobic exercise alters autonomic balance, which may not be favorable in heart rate (HR)-dependent arrhythmic diseases including catecholaminergic polymorphic ventricular tachycardia (CPVT) because of preexisting bradycardia and increased sensitivity to parasympathetic stimulation. OBJECTIVE: The purpose of this study was to determine whether long-term exercise-induced autonomic adaptations modify CPVT susceptibility. METHODS: We determined exercise-induced parasympathetic effects on HR, arrhythmia incidence, and intracellular sarcoplasmic reticulum (SR) Ca2+ leak in atrial (ACM) and ventricular (VCM) cardiomyocytes, in exercised (EX) calsequestrin knockout (CASQ2-/- ) mice, a model of CPVT...
October 10, 2017: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/29025768/action-potential-shortening-and-impairment-of-cardiac-function-by-ablation-of-slc26a6
#9
Padmini Sirish, Hannah A Ledford, Valeriy Timofeyev, Phung N Thai, Lu Ren, Hyo Jeong Kim, Seojin Park, Jeong Han Lee, Gu Dai, Maryam Moshref, Choong-Ryoul Sihn, Wei Chun Chen, Maria Valeryevna Timofeyeva, Zhong Jian, Rafael Shimkunas, Leighton T Izu, Nipavan Chiamvimonvat, Ye Chen-Izu, Ebenezer N Yamoah, Xiao-Dong Zhang
BACKGROUND: Intracellular pH (pHi ) is critical to cardiac excitation and contraction; uncompensated changes in pHi impair cardiac function and trigger arrhythmia. Several ion transporters participate in cardiac pHi regulation. Our previous studies identified several isoforms of a solute carrier Slc26a6 to be highly expressed in cardiomyocytes. We show that Slc26a6 mediates electrogenic Cl- /HCO3 - exchange activities in cardiomyocytes, suggesting the potential role of Slc26a6 in regulation of not only pHi , but also cardiac excitability...
October 2017: Circulation. Arrhythmia and Electrophysiology
https://www.readbyqxmd.com/read/29016724/triggered-intracellular-calcium-waves-in-dog-and-human-left-atrial-myocytes-from-normal-and-failing-hearts
#10
Gary L Aistrup, Rishi Arora, Søren Grubb, Shin Yoo, Benjamin Toren, Manvinder Kumar, Aaron Kunamalla, William Marszalec, Tej Motiwala, Shannon Tai, Sean Yamakawa, Satya Yerrabolu, Francisco J Alvarado, Hector H Valdivia, Jonathan M Cordeiro, Yohannes Shiferaw, John Andrew Wasserstrom
Aims: Abnormal intracellular Ca2+ cycling contributes to triggered activity and arrhythmias in the heart. We investigated the properties and underlying mechanisms for systolic triggered Ca2+ waves in left atria from normal and failing dog hearts. Methods and results: Intracellular Ca2+ cycling was studied using confocal microscopy during rapid pacing of atrial myocytes (36 °C) isolated from normal and failing canine hearts (ventricular tachypacing model). In normal atrial myocytes (NAMs), Ca2+ waves developed during rapid pacing at rates ≥ 3...
November 1, 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28966144/effects-of-exercise-training-on-excitation-contraction-coupling-calcium-dynamics-and-protein-expression-in-the-heart-of-the-neotropical-fish-brycon-amazonicus
#11
Rafael Zanelli Rissoli, Eliton da Silva Vasconcelos, Francisco Tadeu Rantin, Ana Lúcia Kalinin
Matrinxã (Brycon amazonicus) is a great swimming performance teleost fish from the Amazon basin. However, the possible cardiac adaptations of this ability are still unknown. Therefore, the aim of the present work was to investigate the effects of prolonged exercise (EX group - 60days under 0.4BL·s(-1)) on ventricular contractility by (i) in-vitro analysis of contractility comparing the relative roles of sodium/calcium exchanger (NCX) and sarcoplasmic reticulum (SR) in the excitation-contraction (E-C) coupling and (ii) molecular analysis of NCX, sarcoplasmic reticulum Ca(2+) ATPase (SERCA2) and phospholamban (PLB) expression and quantification...
September 29, 2017: Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology
https://www.readbyqxmd.com/read/28964152/minimal-model-for-calcium-alternans-due-to-sr-release-refractoriness
#12
Inma R Cantalapiedra, Enrique Alvarez-Lacalle, Angelina Peñaranda, Blas Echebarria
In the heart, rapid pacing rates may induce alternations in the strength of cardiac contraction, termed pulsus alternans. Often, this is due to an instability in the dynamics of the intracellular calcium concentration, whose transients become larger and smaller at consecutive beats. This alternation has been linked experimentally and theoretically to two different mechanisms: an instability due to (1) a strong dependence of calcium release on sarcoplasmic reticulum (SR) load, together with a slow calcium reuptake into the SR or (2) to SR release refractoriness, due to a slow recovery of the ryanodine receptors (RyR2) from inactivation...
September 2017: Chaos
https://www.readbyqxmd.com/read/28793220/mechanism-for-triggered-waves-in-atrial-myocytes
#13
Yohannes Shiferaw, Gary L Aistrup, J Andrew Wasserstrom
Excitation-contraction coupling in atrial cells is mediated by calcium (Ca) signaling between L-type Ca channels and Ryanodine receptors that occurs mainly at the cell boundary. This unique architecture dictates essential aspects of Ca signaling under both normal and diseased conditions. In this study we apply laser scanning confocal microscopy, along with an experimentally based computational model, to understand the Ca cycling dynamics of an atrial cell subjected to rapid pacing. Our main finding is that when an atrial cell is paced under Ca overload conditions, Ca waves can then nucleate on the cell boundary and propagate to the cell interior...
August 8, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28752958/increased-ca-buffering-underpins-remodelling-of-ca-2-handling-in-old-sheep-atrial-myocytes
#14
Jessica D Clarke, Jessica L Caldwell, Charles M Pearman, David A Eisner, Andrew W Trafford, Katharine M Dibb
KEY POINTS: Ageing is associated with an increased risk of cardiovascular disease and arrhythmias, with the most common arrhythmia being found in the atria of the heart. Little is known about how the normal atria of the heart remodel with age and thus why dysfunction might occur. We report alterations to the atrial systolic Ca(2+) transient that have implications for the function of the atrial in the elderly. We describe a novel mechanism by which increased Ca buffering can account for changes to systolic Ca(2+) in the old atria...
October 1, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28648626/mechanosensitivity-of-microdomain-calcium-signalling-in-the-heart
#15
REVIEW
Patrick Schönleitner, Uli Schotten, Gudrun Antoons
In cardiac myocytes, calcium (Ca2+ ) signalling is tightly controlled in dedicated microdomains. At the dyad, i.e. the narrow cleft between t-tubules and junctional sarcoplasmic reticulum (SR), many signalling pathways combine to control Ca2+ -induced Ca2+ release during contraction. Local Ca2+ gradients also exist in regions where SR and mitochondria are in close contact to regulate energetic demands. Loss of microdomain structures, or dysregulation of local Ca2+ fluxes in cardiac disease, is often associated with oxidative stress, contractile dysfunction and arrhythmias...
November 2017: Progress in Biophysics and Molecular Biology
https://www.readbyqxmd.com/read/28630914/deregulated-ca-2-cycling-underlies-the-development-of-arrhythmia-and-heart-disease-due-to-mutant-obscurin
#16
Li-Yen R Hu, Maegen A Ackermann, Peter A Hecker, Benjamin L Prosser, Brendan King, Kelly A O'Connell, Alyssa Grogan, Logan C Meyer, Christopher E Berndsen, Nathan T Wright, W Jonathan Lederer, Aikaterini Kontrogianni-Konstantopoulos
Obscurins are cytoskeletal proteins with structural and regulatory roles encoded by OBSCN. Mutations in OBSCN are associated with the development of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Specifically, the R4344Q mutation present in immunoglobulin domain 58 (Ig58) was the first to be linked with the development of HCM. To assess the effects of R4344Q in vivo, we generated the respective knock-in mouse model. Mutant obscurins are expressed and incorporated normally into sarcomeres...
June 2017: Science Advances
https://www.readbyqxmd.com/read/28592415/role-of-stim1-stromal-interaction-molecule-1-in-hypertrophy-related-contractile-dysfunction
#17
Constantine D Troupes, Markus Wallner, Giulia Borghetti, Chen Zhang, Sadia Mohsin, Dirk von Lewinski, Remus M Berretta, Hajime Kubo, Xiongwen Chen, Jonathan Soboloff, Steven Houser
RATIONALE: Pathological increases in cardiac afterload result in myocyte hypertrophy with changes in myocyte electrical and mechanical phenotype. Remodeling of contractile and signaling Ca(2+) occurs in pathological hypertrophy and is central to myocyte remodeling. STIM1 (stromal interaction molecule 1) regulates Ca(2+) signaling in many cell types by sensing low endoplasmic reticular Ca(2+) levels and then coupling to plasma membrane Orai channels to induce a Ca(2+) influx pathway. Previous reports suggest that STIM1 may play a role in cardiac hypertrophy, but its role in electrical and mechanical phenotypic alterations is not well understood...
July 7, 2017: Circulation Research
https://www.readbyqxmd.com/read/28550171/%C3%AE-adrenergic-receptor-stimulation-inhibits-proarrhythmic-alternans-in-postinfarction-border-zone-cardiomyocytes-a-computational-analysis
#18
Jakub Tomek, Blanca Rodriguez, Gil Bub, Jordi Heijman
The border zone (BZ) of the viable myocardium adjacent to an infarct undergoes extensive autonomic and electrical remodeling and is prone to repolarization alternans-induced cardiac arrhythmias. BZ remodeling processes may promote or inhibit Ca(2+) and/or repolarization alternans and may differentially affect ventricular arrhythmogenesis. Here, we used a detailed computational model of the canine ventricular cardiomyocyte to study the determinants of alternans in the BZ and their regulation by β-adrenergic receptor (β-AR) stimulation...
August 1, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/28494965/multiscale-determinants-of-delayed-afterdepolarization-amplitude-in-cardiac-tissue
#19
Christopher Y Ko, Michael B Liu, Zhen Song, Zhilin Qu, James N Weiss
Spontaneous calcium (Ca) waves in cardiac myocytes underlie delayed afterdepolarizations (DADs) that trigger cardiac arrhythmias. How these subcellular/cellular events overcome source-sink factors in cardiac tissue to generate DADs of sufficient amplitude to trigger action potentials is not fully understood. Here, we evaluate quantitatively how factors at the subcellular scale (number of Ca wave initiation sites), cellular scale (sarcoplasmic reticulum (SR) Ca load), and tissue scale (synchrony of Ca release in populations of myocytes) determine DAD features in cardiac tissue using a combined experimental and computational modeling approach...
May 9, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28439258/diabetic-cardiomyopathy-an-immunometabolic-perspective
#20
REVIEW
Paras K Mishra, Wei Ying, Shyam Sundar Nandi, Gautam K Bandyopadhyay, Kaushik K Patel, Sushil K Mahata
The heart possesses a remarkable inherent capability to adapt itself to a wide array of genetic and extrinsic factors to maintain contractile function. Failure to sustain its compensatory responses results in cardiac dysfunction, leading to cardiomyopathy. Diabetic cardiomyopathy (DCM) is characterized by left ventricular hypertrophy and reduced diastolic function, with or without concurrent systolic dysfunction in the absence of hypertension and coronary artery disease. Changes in substrate metabolism, oxidative stress, endoplasmic reticulum stress, formation of extracellular matrix proteins, and advanced glycation end products constitute the early stage in DCM...
2017: Frontiers in Endocrinology
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