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("ryanodine receptor" OR "ryr" OR "ryr2") AND ("heart" OR "cardiac")

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https://www.readbyqxmd.com/read/29792814/perspectives-of-a-myosin-motor-activator-agent-with-increased-selectivity
#1
Peter Nanasi, Istvan Komaromi, Janos Almassy
Clinical treatment of heart failure is still not fully solved. A novel class of agents, the myosin motor activators, acts directly on cardiac myosin resulting in an increased force generation and prolongation of contraction. Omecamtiv mecarbil, the lead molecule of this group, is now in human 3 phase displaying promising clinical performance. However, omecamtiv mecarbil is not selective to myosin, since it readily binds to and activates cardiac ryanodine receptors (RyR-2), an effect that may cause complications is case of overdose...
May 24, 2018: Canadian Journal of Physiology and Pharmacology
https://www.readbyqxmd.com/read/29791204/role-of-adenosine-signaling-in-coordinating-cardiomyocyte-function-and-coronary-vascular-growth-in-chronic-fetal-anemia
#2
Lowell Davis, James Musso, Divya Soman, Samantha Louey, Jonathan William Nelson, Sonnet S Jonker
Fetal anemia causes rapid and profound changes in cardiac structure and function, stimulating proliferation of the cardiac myocytes, expansion of the coronary vascular tree, and impairing early contraction and relaxation. While HIF-1α is sure to play a role, adenosine, a metabolic byproduct that increases coronary flow and growth, is implicated as a major stimulus for these adaptations. We hypothesized that genes involved in myocardial adenosine signaling would be up-regulated in chronically anemic fetuses, and that calcium handling genes would be down-regulated...
May 23, 2018: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/29775742/ryanodine-receptor-ca-2-release-channel-post-translational-modification-central-player-in-cardiac-and-skeletal-muscle-disease
#3
Amanda Denniss, Angela F Dulhunty, Nicole A Beard
Calcium release from internal stores is a quintessential event in excitation-contraction coupling in cardiac and skeletal muscle. The ryanodine receptor Ca2+ release channel is embedded in the internal sarcoplasmic reticulum Ca2+ store, which releases Ca2+ into the cytoplasm, enabling contraction. Ryanodine receptors form the hub of a macromolecular complex extending from the extracellular space to the sarcoplasmic reticulum lumen. Ryanodine receptor activity is influenced by the integrated effects of associated co-proteins, ions, and post-translational phosphor and redox modifications...
May 15, 2018: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/29772707/pimt-ncoa6ip-deletion-in-the-mouse-heart-causes-delayed-cardiomyopathy-attributable-to-perturbation-in-energy-metabolism
#4
Yuzhi Jia, Ning Liu, Navin Viswakarma, Ruya Sun, Mathew J Schipma, Meng Shang, Edward B Thorp, Yashpal S Kanwar, Bayar Thimmapaya, Janardan K Reddy
PIMT/NCOA6IP, a transcriptional coactivator PRIP/NCOA6 binding protein, enhances nuclear receptor transcriptional activity. Germline disruption of PIMT results in early embryonic lethality due to impairment of development around blastocyst and uterine implantation stages. We now generated mice with Cre-mediated cardiac-specific deletion of PIMT (csPIMT-/- ) in adult mice. These mice manifest enlargement of heart, with nearly 100% mortality by 7.5 months of age due to dilated cardiomyopathy. Significant reductions in the expression of genes (i) pertaining to mitochondrial respiratory chain complexes I to IV; (ii) calcium cycling cardiac muscle contraction ( Atp2a1 , Atp2a2 , Ryr2 ); and (iii) nuclear receptor PPAR- regulated genes involved in glucose and fatty acid energy metabolism were found in csPIMT-/- mouse heart...
May 16, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29760739/antiarrhythmic-effects-of-carvedilol-and-flecainide-in-cardiomyocytes-derived-from-catecholaminergic-polymorphic-ventricular-tachycardia-patients
#5
R P Pölönen, K Penttinen, H Swan, K Aalto-Setälä
Mutations in the cardiac ryanodine receptor (RYR2) are the leading cause for catecholaminergic polymorphic ventricular tachycardia (CPVT). In this study, we evaluated antiarrhythmic efficacy of carvedilol and flecainide in CPVT patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carrying different mutations in RYR2. iPSC-CMs were generated from skin biopsies of CPVT patients carrying exon 3 deletion and L4115 or V4653F mutation in RYR2 and of a healthy individual. Ca2+ kinetics and drug effects were studied with Fluo-4 AM indicator...
2018: Stem Cells International
https://www.readbyqxmd.com/read/29755362/the-interplay-of-rogue-and-clustered-ryanodine-receptors-regulates-ca-2-waves-in-cardiac-myocytes
#6
Xudong Chen, Yundi Feng, Yunlong Huo, Wenchang Tan
Ca2+ waves in cardiac myocytes can lead to arrhythmias owing to delayed after-depolarisations. Based on Ca2+ regulation from the junctional sarcoplasmic reticulum (JSR), a mathematical model was developed to investigate the interplay of clustered and rogue RyRs on Ca2+ waves. The model successfully reproduces Ca2+ waves in cardiac myocytes, which are in agreement with experimental results. A new wave propagation mode of "spark-diffusion-quark-spark" is put forward. It is found that rogue RyRs greatly increase the initiation of Ca2+ sparks, further contribute to the formation and propagation of Ca2+ waves when the free Ca2+ concentration in JSR lumen ([Ca2+ ]lumen ) is higher than a threshold value of 0...
2018: Frontiers in Physiology
https://www.readbyqxmd.com/read/29748131/underlying-mechanism-of-the-contractile-dysfunction-in-atrophied-ventricular-myocytes-from-a-murine-model-of-hypothyroidism
#7
Dolores Montalvo, Perla Pérez-Treviño, Katheryne Madrazo-Aguirre, Fabio A González-Mondellini, Hipólito O Miranda-Roblero, Diego Ramonfaur-Gracia, Mariana Jacobo-Antonio, Maritza Mayorga-Luna, Norma L Gómez-Víquez, Noemí García, Julio Altamirano
Hypothyroidism (Hypo) is a risk factor for cardiovascular diseases, including heart failure. Hypo rapidly induces Ca2+ mishandling and contractile dysfunction (CD), as well as atrophy and ventricular myocytes (VM) remodeling. Hypo decreases SERCA-to-phospholamban ratio (SERCA/PLB), and thereby contributes to CD. Nevertheless, detailed spatial and temporal Ca2+ cycling characterization in VM is missing, and contribution of other structural and functional changes to the mechanism underlying Ca2+ mishandling and CD, as transverse tubules (T-T) remodeling, mitochondrial density (Dmit ) and energy availability, is unclear...
February 5, 2018: Cell Calcium
https://www.readbyqxmd.com/read/29730419/crispr-cas9-gene-editing-of-ryr2-in-human-stem-cell-derived-cardiomyocytes-provides-a-novel-approach-in-investigating-dysfunctional-ca-2-signaling
#8
Hua Wei, Xiao-Hua Zhang, Cassandra Clift, Naohiro Yamaguchi, Martin Morad
Type-2 ryanodine receptors (RyR2s) play a pivotal role in cardiac excitation-contraction coupling by releasing Ca2+ from sarcoplasmic reticulum (SR) via a Ca2+ -induced Ca2+ release (CICR) mechanism. Two strategies have been used to study the structure-function characteristics of RyR2 and its disease associated mutations: (1) heterologous cell expression of the recombinant mutant RyR2s, and (2) knock-in mouse models harboring RyR2 point mutations. Here, we establish an alternative approach where Ca2+ signaling aberrancy caused by the RyR2 mutation is studied in human cardiomyocytes with robust CICR mechanism...
April 27, 2018: Cell Calcium
https://www.readbyqxmd.com/read/29720499/gene-transfer-of-engineered-calmodulin-alleviates-ventricular-arrhythmias-in-a-calsequestrin-associated-mouse-model-of-catecholaminergic-polymorphic-ventricular-tachycardia
#9
Bin Liu, Shane D Walton, Hsiang-Ting Ho, Andriy E Belevych, Svetlana B Tikunova, Ingrid Bonilla, Vikram Shettigar, Bjorn C Knollmann, Silvia G Priori, Pompeo Volpe, Przemysław B Radwański, Jonathan P Davis, Sándor Györke
BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmogenic syndrome characterized by sudden death. There are several genetic forms of CPVT associated with mutations in genes encoding the cardiac ryanodine receptor (RyR2) and its auxiliary proteins including calsequestrin (CASQ2) and calmodulin (CaM). It has been suggested that impairment of the ability of RyR2 to stay closed (ie, refractory) during diastole may be a common mechanism for these diseases...
May 2, 2018: Journal of the American Heart Association
https://www.readbyqxmd.com/read/29715473/stabilization-of-ca-2-signaling-in-cardiac-muscle-by-stimulation-of-serca
#10
Miguel Fernandez-Tenorio, Ernst Niggli
AIMS: In cardiac muscle, phosphorylation of the RyRs is proposed to increase their Ca2+ sensitivity. This mechanism could be arrhythmogenic via facilitation of spontaneous Ca2+ waves. Surprisingly, the level of Ca2+ inside the SR needed to initiate such waves has been reported to increase upon β-adrenergic stimulation, an observation which cannot be easily reconciled with elevated Ca2+ sensitivity of the RyRs. We tested the hypothesis that this change of Ca2+ wave threshold could occur indirectly, subsequent to SERCA stimulation...
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
#11
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/29674523/efficient-high-throughput-screening-by-er-ca-2-measurement-to-identify-inhibitors-of-ryanodine-receptor-ca2-release-channels
#12
Takashi Murayama, Nagomi Kurebayashi, Mari Ikegami-Yuasa, Shuichi Mori, Yukina Suzuki, Ryunosuke Akima, Haruo Ogawa, Junji Suzuki, Kazunori Kanemaru, Hideto Oyamada, Yuji Kiuchi, Masamitsu Iino, Hiroyuki Kagechika, Takashi Sakurai
Genetic mutations in ryanodine receptors (RyRs), Ca2+-release channels in the sarcoplasmic reticulum essential for muscle contractions, cause various skeletal muscle and cardiac diseases. Because the main underlying mechanism of the pathogenesis is overactive Ca2+ release by gain-of-function of the RyR channel, inhibition of RyRs is expected to be a promising treatment for these diseases. Here, to identify inhibitors specific to skeletal muscle type 1 RyR (RyR1), we developed a novel high-throughput screening (HTS) platform using time-lapse fluorescence measurement of Ca2+ concentrations in the endoplasmic reticulum (ER) ([Ca2+]ER)...
April 19, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29668881/hyperactive-ryanodine-receptors-in-human-heart-failure-and-ischemic-cardiomyopathy-reside-outside-of-couplons
#13
Eef Dries, Demetrio J Santiago, Guillaume Gilbert, Ilse Lenaerts, Bert Vandenberk, Chandan K Nagaraju, Daniel M Johnson, Patricia Holemans, H Llewelyn Roderick, Niall Macquaide, Piet Claus, Karin R Sipido
Aims: In ventricular myocytes from humans and large mammals, the transverse and axial tubular system (TATS) network is less extensive than in rodents with consequently a greater proportion of ryanodine receptors (RyRs) not coupled to this membrane system. TATS remodeling in heart failure (HF) and after myocardial infarction (MI) increases the fraction of non-coupled RyR. Here we investigate whether this remodeling alters the activity of coupled and non-coupled RyR sub-populations through changes in local signaling...
April 14, 2018: Cardiovascular Research
https://www.readbyqxmd.com/read/29668588/a-delayed-diagnosis-of-catecholaminergic-polymorphic-ventricular-tachycardia-with-a-mutant-of-ryr2-at-c-7580t-g-for-6-years-in-a-9-year-old-child
#14
Hongyu Duan, Yongyi Lu, Song Yan, Lina Qiao, Yimin Hua, Yifei Li, Kaiyu Zhou, Chuan Wang
RATIONALE: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare but potentially lethal inherited arrhythmia syndrome induced by adrenergic stress. Due to the atypical clinical manifestations in early age, limited recognition and experience of pediatric cardiologists, and low awareness of the significance of genetic diagnosis in some underdeveloped areas in China, a delayed or missed diagnosis of CPVT in children is common and concerning. PATIENT CONCERNS: A 9-year and 3-month male child with recurrent exercise-induced syncope accompanied by convulsion was initially misdiagnosed as epilepsy since the first manifestation at the age of 3 years...
April 2018: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29653363/trapidil-improves-hemodynamic-echocardiographic-and-redox-state-parameters-of-right-ventricle-in-monocrotaline-induced-pulmonary-arterial-hypertension-model
#15
Patrick Türck, Denise Santos Lacerda, Cristina Campos Carraro, Bruna Gazzi de Lima-Seolin, Rayane Brinck Teixeira, Jéssica Hellen Poletto Bonetto, Rafael Colombo, Paulo Cavalheiro Schenkel, Adriane Belló-Klein, Alex Sander da Rosa Araujo
BACKGROUND: Pulmonary arterial hypertension is a disease characterized by increased pulmonary vascular resistance and redox imbalance, leading to failure of right ventricle. Trapidil has been described to improve the redox balance and cardiac conditions. HYPOTHESIS: Trapidil can improve the redox balance and contribute to functional improvements of the RV in PAH. METHODS AND RESULTS: Male, 5week-old Wistar rats were divided into four groups: Control, Control + Trapidil, Monocrotaline and Monocrotaline + Trapidil...
April 10, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29650543/rbm20-mutations-induce-an-arrhythmogenic-dilated-cardiomyopathy-related-to-disturbed-calcium-handling
#16
Maarten M G van den Hoogenhof, Abdelaziz Beqqali, Ahmad S Amin, Ingeborg van der Made, Simona Aufiero, Mohsin A F Khan, Cees A Schumacher, Joeri A Jansweijer, Karin Y van Spaendonck-Zwarts, Carol Ann Remme, Johannes Backs, Arie O Verkerk, Antonius Baartscheer, Yigal M Pinto, Esther E Creemers
Background -Mutations in RBM20 cause a clinically aggressive form of dilated cardiomyopathy (DCM), with an increased risk of malignant ventricular arrhythmias. RBM20 is a splicing factor that targets multiple pivotal cardiac genes, such as Titin (TTN) and Calcium/calmodulin-dependent kinase II delta (CAMK2D). Aberrant TTN splicing is thought to be the main determinant of RBM20-induced DCM, but is not likely to explain the increased risk of arrhythmias. Here, we investigated the extent at which RBM20 mutation carriers have an increased risk of arrhythmias and explore the underlying molecular mechanism...
April 12, 2018: Circulation
https://www.readbyqxmd.com/read/29593014/ryanodine-receptor-calcium-leak-in-circulating-b-lymphocytes-as-a-biomarker-in-heart-failure
#17
Alexander Kushnir, Gaetano Santulli, Steven R Reiken, Ellie Coromilas, Sarah J Godfrey, Danielle L Brunjes, Paolo C Colombo, Melana Yuzefpolskaya, Seth I Sokol, Richard N Kitsis, Andrew R Marks
Background -Advances in congestive heart failure (CHF) management depend on biomarkers for monitoring disease progression and therapeutic response. During systole, intracellular Ca2+ is released from the sarcoplasmic reticulum (SR) into the cytoplasm through type 2 ryanodine receptor/Ca2+ release channels (RyR2). In CHF, chronically elevated circulating catecholamine levels cause pathologic remodeling of RyR2 resulting in diastolic SR Ca2+ leak, and decreased myocardial contractility. Similarly, skeletal muscle contraction requires SR Ca2+ release through type-1 ryanodine receptors (RyR1), and chronically elevated catecholamine levels in CHF cause RyR1 mediated SR Ca2+ leak, contributing to myopathy and weakness...
March 28, 2018: Circulation
https://www.readbyqxmd.com/read/29590321/polymorphisms-within-ryr3-gene-are-associated-with-risk-and-age-at-onset-of-hypertension-diabetes-and-alzheimer-s-disease
#18
Shaoqing Gong, Brenda Bin Su, Hugo Tovar, ChunXiang Mao, Valeria Gonzalez, Ying Liu, Yongke Lu, Ke-Sheng Wang, Chun Xu
Background: Hypertension affects 33% of Americans while type 2 diabetes and Alzheimer's disease (AD) affect 10% of Americans, respectively. Ryanodine receptor 3 gene (RYR3) codes for the ryanodine receptor which functions to release stored endoplasmic reticulum calcium ions (Ca2+ ) to increase intracellular Ca2+ concentration. Increasing studies demonstrate that altered levels of intracellular Ca2+ affects cardiac contraction, insulin secretion and neurodegeneration. In this study, we investigated associations of the RYR3 genetic variants with hypertension, AD, and diabetes...
March 26, 2018: American Journal of Hypertension
https://www.readbyqxmd.com/read/29549309/coupling-of-sk-channels-l-type-ca-2-channels-and-ryanodine-receptors-in-cardiomyocytes
#19
Xiao-Dong Zhang, Zana A Coulibaly, Wei Chun Chen, Hannah A Ledford, Jeong Han Lee, Padmini Sirish, Gu Dai, Zhong Jian, Frank Chuang, Ingrid Brust-Mascher, Ebenezer N Yamoah, Ye Chen-Izu, Leighton T Izu, Nipavan Chiamvimonvat
Small-conductance Ca2+ -activated K+ (SK) channels regulate the excitability of cardiomyocytes by integrating intracellular Ca2+ and membrane potentials on a beat-to-beat basis. The inextricable interplay between activation of SK channels and Ca2+ dynamics suggests the pathology of one begets another. Yet, the exact mechanistic underpinning for the activation of cardiac SK channels remains unaddressed. Here, we investigated the intracellular Ca2+ microdomains necessary for SK channel activation. SK currents coupled with Ca2+ influx via L-type Ca2+ channels (LTCCs) continued to be elicited after application of caffeine, ryanodine or thapsigargin to deplete SR Ca2+ store, suggesting that LTCCs provide the immediate Ca2+ microdomain for the activation of SK channels in cardiomyocytes...
March 16, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29544605/cardiac-genetic-predisposition-in-sudden-infant-death-syndrome
#20
David J Tester, Leonie C H Wong, Pritha Chanana, Amie Jaye, Jared M Evans, David R FitzPatrick, Margaret J Evans, Peter Fleming, Iona Jeffrey, Marta C Cohen, Jacob Tfelt-Hansen, Michael A Simpson, Elijah R Behr, Michael J Ackerman
BACKGROUND: Sudden infant death syndrome (SIDS) is a leading cause of postneonatal mortality. Genetic heart diseases (GHDs) underlie some cases of SIDS. OBJECTIVES: This study aimed to determine the spectrum and prevalence of GHD-associated mutations as a potential monogenic basis for SIDS. METHODS: A cohort of 419 unrelated SIDS cases (257 male; average age 2.7 ± 1.9 months) underwent whole exome sequencing and a targeted analysis of 90 GHD-susceptibility genes...
March 20, 2018: Journal of the American College of Cardiology
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