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https://www.readbyqxmd.com/read/29753687/istaroxime-a-positive-inotropic-agent-devoid-of-proarrhythmic-properties-in-sensitive-chronic-atrioventricular-block-dogs
#1
Alexandre Bossu, Amée Kostense, Henriette D M Beekman, Marien J C Houtman, Marcel A G van der Heyden, Marc A Vos
Current inotropic agents in heart failure therapy associate with low benefit and significant adverse effects, including ventricular arrhythmias. Istaroxime, a novel Na+ /K+ -transporting ATPase inhibitor, also stimulates SERCA2a activity, which would confer improved inotropic and lusitropic properties with less proarrhythmic effects. We investigated hemodynamic, electrophysiological and potential proarrhythmic and antiarrhythmic effects of istaroxime in control and chronic atrioventricular block (CAVB) dogs sensitive to drug-induced Torsades de Pointes arrhythmias (TdP)...
May 10, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/29723491/qsox1-a-novel-actor-of-cardiac-protection-upon-acute-stress-in-mice
#2
Anais Caillard, Malha Sadoune, Arthur Cescau, Mehdi Meddour, Marine Gandon, Evelyne Polidano, Claude Delcayre, Kelly Da Silva, Philippe Manivet, Ana-Maria Gomez, Alain Cohen-Solal, Nicolas Vodovar, Zhenlin Li, Alexandre Mebazaa, Jane-Lise Samuel
QSOX1, a sulfhydryl oxidase, was shown to be upregulated in the heart upon acute heart failure (AHF). The aim of the study was to unravel QSOX1 roles during AHF. We generated and characterized mice with QSOX1 gene deletion. The QSOX1-/- mice were viable but adult male exhibited a silent dilated cardiomyopathy. The QSOX1-/- hearts were characterized by low protein SERCA2a levels associated with a calcium homeostasis alteration, high levels of the endoplasmic reticulum (ER) chaperone proteins Grp78/Bip, and of the ER apoptosis sensor CHOP, indicating a chronic unfolded protein response (UPR)...
April 30, 2018: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/29686704/the-change-of-left-ventricular-function-in-rats-with-subclinical-hypothyroid-and-the-effects-of-thyroxine-replacement
#3
Xuedi Chen, Cuixia Gao, Ningning Gong, Yu Wang, Limin Tian
Objective: The main purpose of this study was to explore the relationships between serca2a, Ryr2, adipokines, and the left ventricular function in the subclinical hypothyroidism with different TSH levels and to determine the impact of L-T4 treatment on these indexes. Methods: Sixty-five male Wistar rats were randomly divided into five groups: control group; sHT A, B, and C group; and sHT + T4 group. The sHT rats were induced by methimazole (MMI), and the sHT + T4 rats were administered with L-T4 treatment after 8 weeks of MMI administration...
2018: International Journal of Endocrinology
https://www.readbyqxmd.com/read/29674140/impaired-ca-2-cycling-of-nonischemic-myocytes-contributes-to-sarcomere-dysfunction-early-after-myocardial-infarction
#4
Annette Kronenbitter, Florian Funk, Katarzyna Hackert, Simone Gorreßen, Dennis Glaser, Peter Boknik, Gereon Poschmann, Kai Stühler, Malgorzata Isić, Martina Krüger, Joachim P Schmitt
Changes in the nonischemic remote myocardium of the heart contribute to left ventricular dysfunction after ischemia and reperfusion (I/R). Understanding the underlying mechanisms early after I/R is crucial to improve the adaptation of the viable myocardium to increased mechanical demands. Here, we investigated the role of myocyte Ca2+ handling in the remote myocardium 24 h after 60 min LAD occlusion. Cardiomyocytes isolated from the basal noninfarct-related parts of wild type mouse hearts demonstrated depressed beat-to-beat Ca2+ handling...
April 16, 2018: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/29670896/short-term-treatment-with-esmolol-reverses-left-ventricular-hypertrophy-in-adult-spontaneously-hypertensive-rats-via-inhibition-of-akt-nf-%C3%AE%C2%BA-b-and-nfatc4
#5
Begoña Quintana-Villamandos, David A Goukassian, Sharath P Sasi, Emilio Delgado-Baeza
Our group has previously demonstrated that short-term treatment with esmolol reduces left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHRs). The present study aimed to assess the molecular mechanisms related to this effect. Fourteen-month-old male SHRs were treated intravenously with saline as vehicle (SHR) or esmolol (SHR-E) (300  μ g/kg/min). Age-matched vehicle-treated male Wistar-Kyoto (WKY) rats served as controls. After 48 hours of treatment, the hearts were harvested and left ventricular tissue was separated and processed for Western blot analysis to determine the levels of Akt, NF- κ B, NFATc4, Creb1, Serca2a, Erk1/2, and Sapk/Jnk...
2018: BioMed Research International
https://www.readbyqxmd.com/read/29621141/correcting-calcium-dysregulation-in-chronic-heart-failure-using-serca2a-gene-therapy
#6
REVIEW
T Jake Samuel, Ryan P Rosenberry, Seungyong Lee, Zui Pan
Chronic heart failure (CHF) is a major contributor to cardiovascular disease and is the leading cause of hospitalization for those over the age of 65, which is estimated to account for close to seventy billion dollars in healthcare costs by 2030 in the US alone. The successful therapies for preventing and reversing CHF progression are urgently required. One strategy under active investigation is to restore dysregulated myocardial calcium (Ca2+ ), a hallmark of CHF. It is well established that intracellular Ca2+ concentrations are tightly regulated to control efficient myocardial systolic contraction and diastolic relaxation...
April 5, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29538523/melatonin-induced-protective-effects-on-cardiomyocytes-against-reperfusion-injury-partly-through-modulation-of-ip3r-and-serca2a-via-activation-of-erk1
#7
Shunying Hu, Pingjun Zhu, Hao Zhou, Ying Zhang, Yundai Chen
BACKGROUND: Melatonin is a neuroendocrine hormone synthesized primarily by the pineal gland that is indicated to effectively prevent myocardial reperfusion injury. It is unclear whether melatonin protects cardiac function from reperfusion injury by modulating intracellular calcium homeostasis. OBJECTIVE: Demonstrate that melatonin protect against myocardial reperfusion injury through modulating IP3R and SERCA2a to maintain calcium homeostasis via activation of ERK1 in cardiomyocytes...
January 2018: Arquivos Brasileiros de Cardiologia
https://www.readbyqxmd.com/read/29478009/new-insights-into-serca2a-gene-therapy-in-heart-failure-pay-attention-to-the-negative-effects-of-b-type-natriuretic-peptides
#8
Yuting Zhai, Yuanyuan Luo, Pei Wu, Dongye Li
Sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a) is a target of interest in gene therapy for heart failure with reduced ejection fraction (HFrEF). However, the results of an important clinical study, the Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) trial, were controversial. Promising results were observed in the CUPID 1 trial, but the results of the CUPID 2 trial were negative. The factors that caused the controversial results remain unclear. Importantly, enrolled patients were required to have a higher plasma level of B-type natriuretic peptide (BNP) in the CUPID 2 trial...
May 2018: Journal of Medical Genetics
https://www.readbyqxmd.com/read/29475982/lncrna-zfas1-as-a-serca2a-inhibitor-to-cause-intracellular-ca-2-overload-and-contractile-dysfunction-in-a-mouse-model-of-myocardial-infarction
#9
Ying Zhang, Lei Jiao, Lihua Sun, Yanru Li, Yuqiu Gao, Chaoqian Xu, Yingchun Shao, Mengmeng Li, Chunyan Li, Yanjie Lu, Zhenwei Pan, Lina Xuan, Yiyuan Zhang, Qingqi Li, Rui Yang, Yuting Zhuang, Yong Zhang, Baofeng Yang
RATIONALE: Ca2+ homeostasis-a critical determinant of cardiac contractile function-is critically regulated by SERCA2a (sarcoplasmic reticulum Ca2+ -ATPase 2a). Our previous study has identified ZFAS1 as a new lncRNA biomarker of acute myocardial infarction (MI). OBJECTIVE: To evaluate the effects of ZFAS1 on SERCA2a and the associated Ca2+ homeostasis and cardiac contractile function in the setting of MI. METHODS AND RESULTS: ZFAS1 expression was robustly increased in cytoplasm and sarcoplasmic reticulum in a mouse model of MI and a cellular model of hypoxia...
May 11, 2018: Circulation Research
https://www.readbyqxmd.com/read/29450407/changes-in-the-cardiac-ghsr1a-ghrelin-system-correlate-with-myocardial-dysfunction-in-diabetic-cardiomyopathy-in-mice
#10
Rebecca Sullivan, Rebecca McGirr, Shirley Hu, Alice Tan, Derek Wu, Carlie Charron, Tyler Lalonde, Edith Arany, Subrata Chakrabarti, Leonard Luyt, Savita Dhanvantari
Ghrelin and its receptor, the growth hormone secretagogue receptor 1a (GHSR1a), are present in cardiac tissue. Activation of GHSR1a by ghrelin promotes cardiomyocyte contractility and survival, and changes in myocardial GHSR1a and circulating ghrelin track with end-stage heart failure, leading to the hypothesis that GHSR1a is a biomarker for heart failure. We hypothesized that GHSR1a could also be a biomarker for diabetic cardiomyopathy (DCM). We used two models of streptozotocin (STZ)-induced DCM: group 1, adult mice treated with 35 mg/kg STZ for 3 days; and group 2, neonatal mice treated with 70 mg/kg STZ at days 2 and 5 after birth...
February 1, 2018: Journal of the Endocrine Society
https://www.readbyqxmd.com/read/29449318/exosomal-microrna-21-5p-mediates-mesenchymal-stem-cell-paracrine-effects-on-human-cardiac-tissue-contractility
#11
Joshua Mayourian, Delaine K Ceholski, Przemek A Gorski, Prabhu Mathiyalagan, Jack F Murphy, Sophia I Salazar, Francesca Stillitano, Joshua M Hare, Susmita Sahoo, Roger J Hajjar, Kevin D Costa
RATIONALE: The promising clinical benefits of delivering human mesenchymal stem cells (hMSCs) for treating heart disease warrant a better understanding of underlying mechanisms of action. hMSC exosomes increase myocardial contractility; however, the exosomal cargo responsible for these effects remains unresolved. OBJECTIVE: This study aims to identify lead cardioactive hMSC exosomal microRNAs to provide a mechanistic basis for optimizing future stem cell-based cardiotherapies...
March 30, 2018: Circulation Research
https://www.readbyqxmd.com/read/29431258/human-cardiomyocyte-calcium-handling-and-transverse-tubules-in-mid-stage-of-post-myocardial-infarction-heart-failure
#12
Morten Andre Høydal, Idar Kirkeby-Garstad, Asbjørn Karevold, Rune Wiseth, Rune Haaverstad, Alexander Wahba, Tomas L Stølen, Riccardo Contu, Gianluigi Condorelli, Øyvind Ellingsen, Godfrey L Smith, Ole J Kemi, Ulrik Wisløff
AIMS: Cellular processes in the heart rely mainly on studies from experimental animal models or explanted hearts from patients with terminal end-stage heart failure (HF). To address this limitation, we provide data on excitation contraction coupling, cardiomyocyte contraction and relaxation, and Ca2+ handling in post-myocardial-infarction (MI) patients at mid-stage of HF. METHODS AND RESULTS: Nine MI patients and eight control patients without MI (non-MI) were included...
February 12, 2018: ESC Heart Failure
https://www.readbyqxmd.com/read/29421780/luteolin-modulates-serca2a-leading-to-attenuation-of-myocardial-ischemia-reperfusion-injury-via-sumoylation-at-lysine-585-in-mice
#13
Yinping Du, Ping Liu, Tongda Xu, Defeng Pan, Hong Zhu, Nana Zhai, Yanbin Zhang, Dongye Li
BACKGROUND/AIMS: The myocardial sarcoplasmic reticulum calcium ATPase (SERCA2a) is a pivotal pump responsible for calcium cycling in cardiomyocytes. The present study investigated the effect of luteolin (Lut) on restoring SERCA2a protein level and stability reduced by myocardial ischemia/reperfusion (I/R) injury. We verified a hypothesis that Lut protected against myocardial I/R injury by regulating SERCA2a SUMOylation. METHODS: The hemodynamic data, myocardial infarct size of intact hearts, apoptotic analysis, mitochondrial membrane potential (ΔΨm), the level of SERCA2a SUMOylation, and the activity and expression of SERCA2a were examined in vivo and in vitro to clarify the cardioprotective effects of Lut after SUMO1 was knocked down or over-expressed...
2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29410242/sr-ca-2-leak-and-disordered-excitation-contraction-coupling-as-the-basis-for-arrhythmogenic-and-negative-inotropic-effects-of-acute-ethanol-exposure
#14
Julian Mustroph, Olivia Wagemann, Simon Lebek, Daniel Tarnowski, Jasmin Ackermann, Marzena Drzymalski, Steffen Pabel, Christof Schmid, Stefan Wagner, Samuel Sossalla, Lars S Maier, Stefan Neef
AIMS: Ethanol has acute negative inotropic and arrhythmogenic effects. The underlying mechanisms, however, are largely unknown. Sarcoplasmic reticulum Ca2+ -leak is an important mechanism for reduced contractility and arrhythmias. Ca2+ -leak can be induced by oxidative stress and Ca2+ /Calmodulin-dependent protein kinase II (CaMKII). Therefore, we investigated the influence of acute ethanol exposure on excitation-contraction coupling in atrial and ventricular cardiomyocytes. METHODS AND RESULTS: Isolated human atrial and murine atrial or ventricular cardiomyocytes were preincubated for 30 min and then superfused with control solution or solution containing ethanol...
March 2018: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/29385061/hdac-inhibition-improves-the-sarcoendoplasmic-reticulum-ca-2-atpase-activity-in-cardiac-myocytes
#15
Viviana Meraviglia, Leonardo Bocchi, Roberta Sacchetto, Maria Cristina Florio, Benedetta M Motta, Corrado Corti, Christian X Weichenberger, Monia Savi, Yuri D'Elia, Marcelo D Rosato-Siri, Silvia Suffredini, Chiara Piubelli, Giulio Pompilio, Peter P Pramstaller, Francisco S Domingues, Donatella Stilli, Alessandra Rossini
SERCA2a is the Ca2+ ATPase playing the major contribution in cardiomyocyte (CM) calcium removal. Its activity can be regulated by both modulatory proteins and several post-translational modifications. The aim of the present work was to investigate whether the function of SERCA2 can be modulated by treating CMs with the histone deacetylase (HDAC) inhibitor suberanilohydroxamic acid (SAHA). The incubation with SAHA (2.5 µM, 90 min) of CMs isolated from rat adult hearts resulted in an increase of SERCA2 acetylation level and improved ATPase activity...
January 31, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29363575/a-darier-disease-mutation-relieves-kinetic-constraints-imposed-by-the-tail-of-sarco-endo-plasmic-reticulum-ca-2-atpase-2b
#16
Stine A Mikkelsen, Peter Vangheluwe, Jens Peter Andersen
The sarco(endo)plasmic reticulum Ca2+ -ATPase (SERCA) 2b isoform possesses an extended C terminus (SERCA2b tail) forming an 11th transmembrane (TM) helix, which slows conformational changes of the Ca2+ -pump reaction cycle. Here, we report that a Darier disease (DD) mutation of SERCA2b that changes a glutamate to a lysine in the cytoplasmic loop between TM8 and TM9 (E917K) relieves these kinetic constraints. We analyzed the effects of this mutation on the overall reaction and the individual partial reactions of the Ca2+ pump compared with the corresponding mutations of the SERCA2a and SERCA1a isoforms, lacking the SERCA2b tail...
March 16, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29288034/structural-and-functional-remodeling-of-the-atrioventricular-node-with-aging-in-rats-the-role-of-hyperpolarization-activated-cyclic-nucleotide-gated-and-ryanodine-2-channels
#17
Yawer Saeed, Ian Temple, Zoltan Borbas, Andrew Atkinson, Joseph Yanni, Michal Maczewski, Urszula Mackiewicz, Mariam Aly, Sunil J R J Logantha, Clifford Garratt, Halina Dobrzynski
BACKGROUND: Aging is associated with an increased incidence of atrioventricular nodal (AVN) dysfunction. OBJECTIVE: The aim of this study was to investigate the structural and functional remodeling in the atrioventricular junction (AVJ) with aging. METHODS: Electrophysiological, histology, and immunohistochemistry experiments on male Wistar Hannover rats aged 3 months (n = 24) and 2 years (n = 15) were performed. Atrio-His (AH) interval, Wenkebach cycle length (WBCL), and AVN effective refractory period (AVNERP) were measured...
December 27, 2017: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/29273502/mir-25-tough-decoy-enhances-cardiac-function-in-heart-failure
#18
Dongtak Jeong, Jimeen Yoo, Philyoung Lee, Sacha V Kepreotis, Ahyoung Lee, Christine Wahlquist, Brian D Brown, Changwon Kho, Mark Mercola, Roger J Hajjar
MicroRNAs are promising therapeutic targets, because their inhibition has the potential to normalize gene expression in diseased states. Recently, our group found that miR-25 is a key SERCA2a regulating microRNA, and we showed that multiple injections of antagomirs against miR-25 enhance cardiac contractility and function through SERCA2a restoration in a murine heart failure model. However, for clinical application, a more stable suppressor of miR-25 would be desirable. Tough Decoy (TuD) inhibitors are emerging as a highly effective method for microRNA inhibition due to their resistance to endonucleolytic degradation, high miRNA binding affinity, and efficient delivery...
March 7, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29249393/therapeutic-benefit-and-gene-network-regulation-by-combined-gene-transfer-of-apelin-fgf2-and-serca2a-into-ischemic-heart
#19
Edith Renaud-Gabardos, Florence Tatin, Fransky Hantelys, Benoît Lebas, Denis Calise, Oksana Kunduzova, Bernard Masri, Françoise Pujol, Pierre Sicard, Philippe Valet, Jérôme Roncalli, Xavier Chaufour, Barbara Garmy-Susini, Angelo Parini, Anne-Catherine Prats
Despite considerable advances in cardiovascular disease treatment, heart failure remains a public health challenge. In this context, gene therapy appears as an attractive approach, but clinical trials using single therapeutic molecules result in moderate benefit. With the objective of improving ischemic heart failure therapy, we designed a combined treatment, aimed to simultaneously stimulate angiogenesis, prevent cardiac remodeling, and restore contractile function. We have previously validated IRES-based vectors as powerful tools to co-express genes of interest...
March 7, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29229678/epitope-mapping-of-serca2a-identifies-an-antigenic-determinant-that-induces-mainly-atrial-myocarditis-in-a-j-mice
#20
Bharathi Krishnan, Chandirasegaran Massilamany, Rakesh H Basavalingappa, Arunakumar Gangaplara, Rajkumar A Rajasekaran, Muhammad Z Afzal, Vahid Khalilzad-Sharghi, You Zhou, Jean-Jack Riethoven, Shyam S Nandi, Paras K Mishra, Raymond A Sobel, Jennifer L Strande, David Steffen, Jay Reddy
Sarcoplasmic/endoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA)2a, a critical regulator of calcium homeostasis, is known to be decreased in heart failure. Patients with myocarditis or dilated cardiomyopathy develop autoantibodies to SERCA2a suggesting that they may have pathogenetic significance. In this report, we describe epitope mapping analysis of SERCA2a in A/J mice that leads us to make five observations: 1) SERCA2a contains multiple T cell epitopes that induce varying degrees of myocarditis...
January 15, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
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