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https://www.readbyqxmd.com/read/27910039/silencing-genes-in-the-heart
#1
Henry Fechner, Roland Vetter, Jens Kurreck, Wolfgang Poller
Silencing of cardiac genes by RNA interference (RNAi) has developed into a powerful new method to treat cardiac diseases. Small interfering (si)RNAs are the inducers of RNAi, but cultured primary cardiomyocytes and heart are highly resistant to siRNA transfection. This can be overcome by delivery of small hairpin (sh)RNAs or artificial microRNA (amiRNAs) by cardiotropic adeno-associated virus (AAV) vectors. Here we describe as example of the silencing of a cardiac gene, the generation and cloning of shRNA, and amiRNAs directed against the cardiac protein phospholamban...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27908653/molecular-changes-in-children-with-heart-failure-undergoing-left-ventricular-assist-device-therapy
#2
Elizabeth Medina, Carmen C Sucharov, Penny Nelson, Shelley D Miyamoto, Brian L Stauffer
OBJECTIVE: To determine whether left ventricular assist device (LVAD) treatment in children with heart failure would result in the modification of molecular pathways involved in heart failure pathophysiology. STUDY DESIGN: Forty-seven explanted hearts from children were studied (16 nonfailing control, 20 failing, and 11 failing post-LVAD implantation [F-LVAD]). Protein expression and phosphorylation states were determined by receptor binding assays and Western blots...
November 29, 2016: Journal of Pediatrics
https://www.readbyqxmd.com/read/27864509/loss-of-%C3%AE-adrenergic-stimulated-phosphorylation-of-cav1-2-channels-on-ser1700-leads-to-heart-failure
#3
Linghai Yang, Dao-Fu Dai, Can Yuan, Ruth E Westenbroek, Haijie Yu, Nastassya West, Horacio O de la Iglesia, William A Catterall
L-type Ca(2+) currents conducted by voltage-gated calcium channel 1.2 (CaV1.2) initiate excitation-contraction coupling in the heart, and altered expression of CaV1.2 causes heart failure in mice. Here we show unexpectedly that reducing β-adrenergic regulation of CaV1.2 channels by mutation of a single PKA site, Ser1700, in the proximal C-terminal domain causes reduced contractile function, cardiac hypertrophy, and heart failure without changes in expression, localization, or function of the CaV1.2 protein in the mutant mice (SA mice)...
November 18, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27856611/loss-of-akap150-promotes-pathological-remodelling-and-heart-failure-propensity-by-disrupting-calcium-cycling-and-contractile-reserve
#4
Lei Li, Jing Li, Benjamin M Drum, Yi Chen, Haifeng Yin, Xiaoyun Guo, Stephen W Luckey, Merle L Gilbert, G Stanley McKnight, John D Scott, L Fernando Santana, Qinghang Liu
AIMS: Impaired Ca(2 + )cycling and myocyte contractility are a hallmark of heart failure triggered by pathological stress such as hemodynamic overload. The A-Kinase anchoring protein AKAP150 has been shown to coordinate key aspects of adrenergic regulation of Ca(2+ )cycling and excitation-contraction in cardiomyocytes. However, the role of the AKAP150 signalling complexes in the pathogenesis of heart failure has not been investigated. METHODS AND RESULTS: Here we examined how AKAP150 signalling complexes impact Ca(2+ )cycling, myocyte contractility, and heart failure susceptibility following pathological stress...
November 17, 2016: Cardiovascular Research
https://www.readbyqxmd.com/read/27833092/molecular-inotropy-mediated-by-cardiac-mir-based-pde4d-prkar1%C3%AE-phosphoprotein-signaling
#5
Fikru B Bedada, Joshua J Martindale, Erik Arden, Joseph M Metzger
Molecular inotropy refers to cardiac contractility that can be modified to affect overall heart pump performance. Here we show evidence of a new molecular pathway for positive inotropy by a cardiac-restricted microRNA (miR). We report enhanced cardiac myocyte performance by acute titration of cardiac myosin-embedded miR-208a. The observed positive effect was independent of host gene myosin effects with evidence of negative regulation of cAMP-specific 3',5'-cyclic phosphodiesterase 4D (PDE4D) and the regulatory subunit of PKA (PRKAR1α) content culminating in PKA-site dependent phosphorylation of cardiac troponin I (cTnI) and phospholamban (PLN)...
November 11, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27815373/inhibiting-insulin-mediated-%C3%AE-2ar-activation-prevents-diabetes-associated-cardiac-dysfunction
#6
Qingtong Wang, Yongming Liu, Qin Fu, Bing Xu, Yuan Zhang, Sungjin Kim, Ruensern Tan, Federica Barbagallo, Toni M West, Ethan J Anderson, Wei Wei, E Dale Abel, Yang K Xiang
BACKGROUND: -Type-2 diabetes and obesity independently increases the risk of heart failure via incompletely understood mechanisms. We propose that hyperinsulinemia might promote adverse consequences in hearts of subjects with type-2 diabetes and obesity. METHODS: -High fat diet feeding was used to induce obesity and diabetes in wild type mice or mice lacking β 2-adrenergic receptor (β2AR) or β -arrestin2. Wild type mice fed with high fat diet were treated with β -blocker carvedilol or G-protein receptor kinase 2 (GRK2) inhibitor...
November 4, 2016: Circulation
https://www.readbyqxmd.com/read/27811197/phospholamban-inhibition-by-a-single-dose-of-locked-nucleic-acid-antisense-oligonucleotide-improves-cardiac-contractility-in-pressure-overload-induced-systolic-dysfunction-in-mice
#7
Hirofumi Morihara, Tsuyoshi Yamamoto, Harunori Oiwa, Kota Tonegawa, Daisuke Tsuchiyama, Ikki Kawakatsu, Masanori Obana, Makiko Maeda, Tomomi Mohri, Satoshi Obika, Yasushi Fujio, Hiroyuki Nakayama
BACKGROUND: Phospholamban (PLN) inhibition enhances calcium cycling and is a potential novel therapy for heart failure (HF). Antisense oligonucleotides (ASOs) are a promising tool for unmet medical needs. Nonviral vector use of locked nucleic acid (LNA)-modified ASOs (LNA-ASOs), which shows strong binding to target RNAs and is resistant to nuclease, is considered to have a potential for use in novel therapeutics in the next decades. Thus, the efficacy of a single-dose injection of LNA-ASO for cardiac disease needs to be elucidated...
November 2, 2016: Journal of Cardiovascular Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27782102/disulfide-activated-protein-kinase-g-i%C3%AE-regulates-cardiac-diastolic-relaxation-and-fine-tunes-the-frank-starling-response
#8
Jenna Scotcher, Oleksandra Prysyazhna, Andrii Boguslavskyi, Kornel Kistamas, Natasha Hadgraft, Eva D Martin, Jenny Worthington, Olena Rudyk, Pedro Rodriguez Cutillas, Friederike Cuello, Michael J Shattock, Michael S Marber, Maria R Conte, Adam Greenstein, David J Greensmith, Luigi Venetucci, John F Timms, Philip Eaton
The Frank-Starling mechanism allows the amount of blood entering the heart from the veins to be precisely matched with the amount pumped out to the arterial circulation. As the heart fills with blood during diastole, the myocardium is stretched and oxidants are produced. Here we show that protein kinase G Iα (PKGIα) is oxidant-activated during stretch and this form of the kinase selectively phosphorylates cardiac phospholamban Ser16-a site important for diastolic relaxation. We find that hearts of Cys42Ser PKGIα knock-in (KI) mice, which are resistant to PKGIα oxidation, have diastolic dysfunction and a diminished ability to couple ventricular filling with cardiac output on a beat-to-beat basis...
October 26, 2016: Nature Communications
https://www.readbyqxmd.com/read/27775022/proteomic-and-phosphoproteomic-analysis-of-renal-cortex-in-a-salt-load-rat-model-of-advanced-kidney-damage
#9
Shaoling Jiang, Hanchang He, Lishan Tan, Liangliang Wang, Zhengxiu Su, Yufeng Liu, Hongguo Zhu, Menghuan Zhang, Fan Fan Hou, Aiqing Li
Salt plays an essential role in the progression of chronic kidney disease and hypertension. However, the mechanisms underlying pathogenesis of salt-induced kidney damage remain largely unknown. Here, Sprague-Dawley rats, that underwent 5/6 nephrectomy (5/6Nx, a model of advanced kidney damage) or sham operation, were treated for 2 weeks with a normal or high-salt diet. We employed aTiO2 enrichment, iTRAQ labeling and liquid-chromatography tandem mass spectrometry strategy for proteomic and phosphoproteomic profiling of the renal cortex...
October 24, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27761848/dexamethasone-induced-cardiac-deterioration-is-associated-with-both-calcium-handling-abnormalities-and-calcineurin-signaling-pathway-activation
#10
Fabiana de Salvi Guimarães, Wilson Max Almeida Monteiro de Moraes, Luis Henrique Marchesi Bozi, Pâmela R Souza, Ednei Luiz Antonio, Danilo Sales Bocalini, Paulo José Ferreira Tucci, Daniel Araki Ribeiro, Patricia Chakur Brum, Alessandra Medeiros
Dexamethasone is a potent and widely used anti-inflammatory and immunosuppressive drug. However, recent evidences suggest that dexamethasone cause pathologic cardiac remodeling, which later impairs cardiac function. The mechanism behind the cardiotoxic effect of dexamethasone is elusive. The present study aimed to verify if dexamethasone-induced cardiotoxicity would be associated with changes in the cardiac net balance of calcium handling protein and calcineurin signaling pathway activation. Wistar rats (~400 g) were treated with dexamethasone (35 µg/g) in drinking water for 15 days...
October 19, 2016: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/27746188/disruption-of-calcium-homeostasis-by-cardiac-specific-over-expression-of-ppar-%C3%AE-in-mice-a-role-in-ventricular-arrhythmia
#11
Yong Xie, Zhen-Jie Gu, Mao-Xiong Wu, Tu-Cheng Huang, Jing-Song Ou, Huiping-Son Ni, Mao-Huan Lin, Wo-Liang Yuan, Jing-Feng Wang, Yang-Xin Chen
AIMS: Adverse cardiovascular effects induced by peroxisome proliferator activator receptor-γ (PPAR-γ) activation were observed in clinical setting. But the underlying mechanism is unclear. Now, transgenic mice with cardiac specific peroxisome proliferator activator receptor-γ overexpression (TG-PPAR-γ) were used to explore the possible mechanisms. MATERIALS AND METHODS: Cardiac tissues from TG-PPAR-γ mice, a PPAR-γ over-expressing human cardiomyocyte line AC16 cell, and PPAR-γ agonist-treated primary cardiomyocytes were used to evaluate the expression of cardiac calcium regulatory proteins as sarcoplasmic reticulum Ca(2+) ATPase, Na(+)/Ca(2+)exchanger 1, ryanodine receptor 2 and phospholamban...
October 13, 2016: Life Sciences
https://www.readbyqxmd.com/read/27742792/global-phosphoproteomic-profiling-reveals-perturbed-signaling-in-a-mouse-model-of-dilated-cardiomyopathy
#12
Uros Kuzmanov, Hongbo Guo, Diana Buchsbaum, Jake Cosme, Cynthia Abbasi, Ruth Isserlin, Parveen Sharma, Anthony O Gramolini, Andrew Emili
Phospholamban (PLN) plays a central role in Ca(2+) homeostasis in cardiac myocytes through regulation of the sarco(endo)plasmic reticulum Ca(2+)-ATPase 2A (SERCA2A) Ca(2+) pump. An inherited mutation converting arginine residue 9 in PLN to cysteine (R9C) results in dilated cardiomyopathy (DCM) in humans and transgenic mice, but the downstream signaling defects leading to decompensation and heart failure are poorly understood. Here we used precision mass spectrometry to study the global phosphorylation dynamics of 1,887 cardiac phosphoproteins in early affected heart tissue in a transgenic R9C mouse model of DCM compared with wild-type littermates...
October 14, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27729868/the-autonomic-nervous-system-regulates-the-heart-rate-through-camp-pka-dependent-and-independent-coupled-clock-pacemaker-cell-mechanisms
#13
Joachim Behar, Ambhighainath Ganesan, Jin Zhang, Yael Yaniv
Sinoatrial nodal cells (SANCs) generate spontaneous action potentials (APs) that control the cardiac rate. The brain modulates SANC automaticity, via the autonomic nervous system, by stimulating membrane receptors that activate (adrenergic) or inactivate (cholinergic) adenylyl cyclase (AC). However, these opposing afferents are not simply additive. We showed that activation of adrenergic signaling increases AC-cAMP/PKA signaling, which mediates the increase in the SANC AP firing rate (i.e., positive chronotropic modulation)...
2016: Frontiers in Physiology
https://www.readbyqxmd.com/read/27723783/increase-in-cardiac-ischemia-reperfusion-injuries-in-opa1-mouse-model
#14
Sophie Le Page, Marjorie Niro, Jérémy Fauconnier, Laura Cellier, Sophie Tamareille, Abdallah Gharib, Arnaud Chevrollier, Laurent Loufrani, Céline Grenier, Rima Kamel, Emmanuelle Sarzi, Alain Lacampagne, Michel Ovize, Daniel Henrion, Pascal Reynier, Guy Lenaers, Delphine Mirebeau-Prunier, Fabrice Prunier
BACKGROUND: Recent data suggests the involvement of mitochondrial dynamics in cardiac ischemia/reperfusion (I/R) injuries. Whilst excessive mitochondrial fission has been described as detrimental, the role of fusion proteins in this context remains uncertain. OBJECTIVES: To investigate whether Opa1 (protein involved in mitochondrial inner-membrane fusion) deficiency affects I/R injuries. METHODS AND RESULTS: We examined mice exhibiting Opa1delTTAG mutations (Opa1+/-), showing 70% Opa1 protein expression in the myocardium as compared to their wild-type (WT) littermates...
2016: PloS One
https://www.readbyqxmd.com/read/27688314/genotype-dependent-and-independent-calcium-signaling-dysregulation-in-human-hypertrophic-cardiomyopathy
#15
Adam S Helms, Francisco J Alvarado, Jaime Yob, Vi T Tang, Francis Pagani, Mark W Russell, Héctor H Valdivia, Sharlene M Day
BACKGROUND: Aberrant calcium signaling may contribute to arrhythmias and adverse remodeling in hypertrophic cardiomyopathy (HCM). Mutations in sarcomere genes may distinctly alter calcium handling pathways. METHODS: We analyzed gene expression, protein levels, and functional assays for calcium regulatory pathways in human HCM surgical samples with (n=25) and without (n=10) sarcomere mutations compared with control hearts (n=8). RESULTS: Gene expression and protein levels for calsequestrin, L-type calcium channel, sodium-calcium exchanger, phospholamban, calcineurin, and calcium/calmodulin-dependent protein kinase type II (CaMKII) were similar in HCM samples compared with controls...
November 29, 2016: Circulation
https://www.readbyqxmd.com/read/27667273/-tetrahydrobiopterin-improves-left-ventricular-diastolic-function-possibly-through-upregulating-phosphorylated-protein-kinase-b-expression-in-hypertensive-mice-induced-by-deoxycorticosterone-acetate
#16
Q Y Wang, M N Yang, H Xu, Y Zhao, X Lin, X W Zhang, F Zhao, X Zhao, X Q Kou, F Bai, J Yu
Objective: To investigate whether tetrahydrobiopterin (BH4) could improve left ventricular diastolic function through phosphoinositide-3 kinase/protein kinase B (PI3K/Akt) signaling pathway in hypertensive mice. Methods: Ten-week-old male C57BL/6 mice were used to establish the deoxycorticosterone acetate (DOCA)-salt hypertensive model, age matched Sham mice serve as the controls. Mice were divided into four groups: Sham(n=20), Sham+ BH4 (n=20), DOCA (n=22), and DOCA+ BH4 (n=22). On the 14 days after surgery, mice in Sham+ BH4 and DOCA+ BH4 groups received BH4 (0...
September 24, 2016: Zhonghua Xin Xue Guan Bing za Zhi
https://www.readbyqxmd.com/read/27643434/axial-tubule-junctions-control-rapid-calcium-signaling-in-atria
#17
Sören Brandenburg, Tobias Kohl, George S B Williams, Konstantin Gusev, Eva Wagner, Eva A Rog-Zielinska, Elke Hebisch, Miroslav Dura, Michael Didié, Michael Gotthardt, Viacheslav O Nikolaev, Gerd Hasenfuss, Peter Kohl, Christopher W Ward, W Jonathan Lederer, Stephan E Lehnart
The canonical atrial myocyte (AM) is characterized by sparse transverse tubule (TT) invaginations and slow intracellular Ca2+ propagation but exhibits rapid contractile activation that is susceptible to loss of function during hypertrophic remodeling. Here, we have identified a membrane structure and Ca2+-signaling complex that may enhance the speed of atrial contraction independently of phospholamban regulation. This axial couplon was observed in human and mouse atria and is composed of voluminous axial tubules (ATs) with extensive junctions to the sarcoplasmic reticulum (SR) that include ryanodine receptor 2 (RyR2) clusters...
October 3, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27642167/phospholamban-is-concentrated-in-the-nuclear-envelope-of-cardiomyocytes-and-involved-in-perinuclear-nuclear-calcium-handling
#18
Adonis Z Wu, Dongzhu Xu, Na Yang, Shien-Fong Lin, Peng-Sheng Chen, Steven E Cala, Zhenhui Chen
AIMS: Phospholamban (PLB) regulates the cardiac Ca(2+)-ATPase (SERCA2a) in sarcoplasmic reticulum (SR). However, the localization of PLB at subcellular sites outside the SR and possible contributions to Ca(2+) cycling remain unknown. We examined the intracellular distribution of PLB and tested whether a pool of PLB exists in the nuclear envelope (NE) that might regulate perinuclear/nuclear Ca(2+) (nCa(2+)) handling in cardiomyocytes (CMs). METHODS AND RESULTS: Using confocal immunofluorescence microscopy and immunoblot analyses of CMs and CM nuclei, we discovered that PLB was highly concentrated in NE...
September 15, 2016: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/27614224/hyperaldosteronism-induces-left-atrial-systolic-and-diastolic-dysfunction
#19
Jan-Christian Reil, Marcus Tauchnitz, Qinghai Tian, Mathias Hohl, Dominik Linz, Martin Oberhofer, Lars Kaestner, Gert-Hinrich Reil, Holger Thiele, Paul Steendijk, Michael Böhm, Hans-Ruprecht Neuberger, Peter Lipp
Patients with hypertension and hyperaldosteronism show an increased risk of stroke compared with patients with essential hypertension. Aim of the study was to assess the effects of aldosterone on left atrial function in rats as a potential contributor to thromboembolism. Osmotic mini-pumps delivering 1.5 μg aldosterone/h were implanted in rats subcutaneously (Aldo, n = 39; controls, n = 38). After 8 wk, left ventricular pressure-volume analysis of isolated working hearts was performed, and left atrial systolic and diastolic function was also assessed by atrial pressure-diameter loops...
October 1, 2016: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/27595734/vasostatin-1-stops-structural-remodeling-and-improves-calcium-handling-via-the-enos-no-pkg-pathway-in-rat-hearts-subjected-to-chronic-%C3%AE-adrenergic-receptor-activation
#20
Dandan Wang, Yingguang Shan, Yan Huang, Yanhong Tang, Yuting Chen, Ran Li, Jing Yang, Congxin Huang
PURPOSE: Chronically elevated catecholamine levels activate cardiac β-adrenergic receptors, which play a vital role in the pathogenesis of heart failure. Evidence suggests that vasostatin-1 (VS-1) exerts anti-adrenergic effects on isolated and perfused hearts in vitro. Whether VS-1 ameliorates hypertrophy/remodeling by inducing the chronic activation of β-adrenergic receptors is unknown. The present study aims to test the efficacy of using VS-1 to treat the advanced hypertrophy/remodeling that result from chronic β-adrenergic receptor activation and to determine the cellular and molecular mechanisms that underlie this response...
October 2016: Cardiovascular Drugs and Therapy
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