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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
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...
February 24, 2018: Journal of Medical Genetics
Ying Zhang, Lei Jiao, Li-Hua Sun, Yanru Li, Yuqiu Gao, Chaoqian Xu, Yingchun Shao, Mengmeng Li, Chunyan Li, Yanjie Lu, Zhenwei Pan, Li-Na Xuan, Yiyuan Zhang, Qingqi Li, Rui Yang, Yuting Zhuang, Yong Zhang, Baofeng Yang
<u>Rationale:</u> Ca2+ homeostasis, a critical determinant of cardiac contractile function, is critically regulated by sarcoplasmic reticulum Ca2+ -ATPase 2a (SERCA2a). Our previous study has identified ZFAS1 as a new long non-coding RNA (lncRNA) biomarker of acute myocardial infarction (MI). <u>Objective:</u> To evaluate the effects of ZFAS1 on SERCA2a and the associated Ca2+ homeostasis and cardiac contractile function in the setting of MI. <u>Methods and Results:</u> ZFAS1 expression was robustly increased in cytoplasm and sarcoplasmic reticulum in a mouse model of MI and a cellular model of hypoxia...
February 23, 2018: Circulation Research
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
Joshua Mayourian, Delaine K Ceholski, Przemyslaw Gorski, Prabhu Mathiyalagan, Jack F Murphy, Sophia I Salazar, Francesca Stillitano, Joshua M Hare, Susmita Sahoo, Roger J Hajjar, Kevin D Costa
<u>Rationale:</u> 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. <u>Objective:</u> This study aims to identify lead cardioactive hMSC exosomal microRNAs to provide a mechanistic basis for optimizing future stem cell-based cardiotherapies...
February 15, 2018: Circulation Research
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
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...
February 2, 2018: Cellular Physiology and Biochemistry
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...
February 2, 2018: Journal of Molecular and Cellular Cardiology
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
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 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...
January 23, 2018: Journal of Biological Chemistry
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: Ageing is associated with an increased incidence of atrioventricular nodal (AVN) dysfunction. OBJECTIVES: The aim of the study is to identify the structural and functional remodelling in the atrioventricular junction (AVJ) with ageing. METHODS: Electrophysiological, histology and immunohistochemistry experiments on male Wistar-Hanover rats aged 3months (n=24) and 2years (n=15) were performed. AH interval, Wenkebach cycle length (WBCL) and AVN effective refractory period (AVNERP) were measured...
December 26, 2017: Heart Rhythm: the Official Journal of the Heart Rhythm Society
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...
November 26, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
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...
November 16, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
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
Subhash K Das, Pavel Zhabyeyev, Ratnadeep Basu, Vaibhav B Patel, Jason R B Dyck, Zamaneh Kassiri, Gavin Y Oudit
Iron-overload cardiomyopathy is prevalent on a worldwide basis and is a major comorbidity in patients with genetic hemochromatosis and secondary iron overload. Therapies are limited in part due to lack of a valid preclinical model, which recapitulates advanced iron-overload cardiomyopathy. Male hemojuvelin (HJV) knockout (HJVKO) mice, which lack HJV, a bone morphogenetic co-receptor protein required for hepcidin expression and systemic iron homeostasis, were fed a high-iron diet starting at 4 weeks of age for a duration of 1 year...
February 28, 2018: Bioscience Reports
Florentina Pluteanu, Yulia Nikonova, Anna Holzapfel, Birgit Herzog, Anna Scherer, Judit Preisenberger, Jelena Plačkić, Katharina Scheer, Teodora Ivanova, Alicja Bukowska, Andreas Goette, Jens Kockskämper
Hypertensive heart disease (HHD) can cause left ventricular (LV) hypertrophy and heart failure (HF). It is unclear, though, which factors may contribute to the transition from compensated LV hypertrophy to HF in HHD. We hypothesized that maladaptive atrial remodeling with impaired atrial myocyte function would occur in advanced HHD and may be associated with the emergence of HF. Experiments were performed on atrial myocytes and tissue from old (15-25months) normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) with advanced HHD...
January 2018: Journal of Molecular and Cellular Cardiology
Lu Wang, Yurong Cui, Qinghua Liu, Yuanlong Song, Qinghua Hu, Ming Tang, Jürgen Hescheler, Jiaoya Xi
BACKGROUND/AIMS: The embryonic stem cell-derived cardiomyocytes (ES-CMs) serve as potential sources for cardiac regenerative therapy. However, the immature sarcoplasmic reticulum (SR) function of ES-CMs prevents its application. In this report, we examined the effect of puerarin, an isoflavone compound, on SR function of murine ES-CMs. METHODS: Murine ES-CMs were harvested by embryoid body-based differentiation method. Confocal calcium imaging and whole-cell patch clamps were performed to assess the function of SR...
2017: Cellular Physiology and Biochemistry
Zhaohui Pei, Qinqin Deng, Sara A Babcock, Emily Y He, Jun Ren, Yingmei Zhang
Diabetes mellitus leads to oxidative stress and contractile dysfunction in the heart. Although several rationales have been speculated, the precise mechanism behind diabetic cardiomyopathy remains elusive. This study was designed to assess the role of inhibition of advanced glycation endproducts (AGE) in streptozotocin (STZ)-induced diabetic cardiac dysfunction. Cardiac contractile function was assessed in normal C57BL/6 and STZ (200mg/kg, single injection and maintained for 2 wks)-induced diabetic mice treated with or without the AGE inhibitor aminoguanidine (50mg/kg/d in drinking water) for 2 weeks using echocardiography and IonOptix MyoCam techniques...
March 1, 2018: Toxicology Letters
Philip A Bidwell, Guan-Sheng Liu, Narayani Nagarajan, Chi Keung Lam, Kobra Haghighi, George Gardner, Wen-Feng Cai, Wen Zhao, Luke Mugge, Elizabeth Vafiadaki, Despina Sanoudou, Jack Rubinstein, Djamel Lebeche, Roger Hajjar, Junichi Sadoshima, Evangelia G Kranias
Ischemia/reperfusion injury is associated with contractile dysfunction and increased cardiomyocyte death. Overexpression of the hematopoietic lineage substrate-1-associated protein X-1 (HAX-1) has been shown to protect from cellular injury but the function of endogenous HAX-1 remains obscure due to early lethality of the knockout mouse. Herein we generated a cardiac-specific and inducible HAX-1 deficient model, which uncovered an unexpected role of HAX-1 in regulation of sarco/endoplasmic reticulum Ca-ATPase (SERCA2a) in ischemia/reperfusion injury...
January 2018: Journal of Molecular and Cellular Cardiology
Shin-Haw Lee, Sina Hadipour-Lakmehsari, Tetsuaki Miyake, Anthony O Gramolini
The mammalian nucleus has invaginations from the cytoplasm, termed nucleoplasmic reticulum (NR). With increased resolution of cellular imaging, progress has been made in understanding the formation and function of NR. In fact, nucleoplasmic Ca2+ homeostasis has been implicated in the regulation of gene expression, DNA repair, and cell death. However, the majority of studies focus on cross-sectional or single plane analyses of NR invaginations, providing an incomplete assessment of its distribution and content...
November 22, 2017: American Journal of Physiology. Cell Physiology
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