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Circulation Research

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https://www.readbyqxmd.com/read/28630135/inhibition-of-the-cardiac-fibroblast-enriched-lncrna-meg3-prevents-cardiac-fibrosis-and-diastolic-dysfunction
#1
Maria-Teresa Piccoli, Shashi Gupta, Janika Viereck, Ariana Foinquinos, Sabine Samolovac, Freya Kramer, Ankita Garg, Janet Remke, Karina Zimmer, Sandor Batkai, Thomas Thum
Rationale: Cardiac fibroblasts (CFs) drive extracellular matrix (ECM) remodeling following pressure overload, leading to fibrosis and diastolic dysfunction. Recent studies described the role of long noncoding RNAs (lncRNAs) in cardiac pathologies. Nevertheless, detailed reports on lncRNAs regulating CF biology and describing their implication in cardiac remodeling are still missing. Objective: Here, we aimed at characterizing lncRNA expression in murine CFs following chronic pressure overload, in order to identify CF-enriched lncRNAs and investigate their function and contribution to cardiac fibrosis and diastolic dysfunction...
June 19, 2017: Circulation Research
https://www.readbyqxmd.com/read/28620068/x-box-binding-protein-1-dependent-plasma-cell-responses-limit-the-development-of-atherosclerosis
#2
Andrew P Sage, Meritxell Nus, Jayashree Bagchi Chakraborty, Dimitrios Tsiantoulas, Stephen A Newland, Alison J Finigan, Leanne Masters, Christoph J Binder, Ziad Mallat
Rationale: Diverse B cell responses and functions may be involved in atherosclerosis. Protective antibody responses, such as those against oxidized lipid epitopes, are thought to mainly derive from T cell-independent innate B cell subsets. In contrast, both pathogenic and protective roles have been associated with T cell-dependent antibodies and their importance in both humans and mouse models is still unclear. Objective: To specifically target antibody production by plasma cells and determine the impact on atherosclerotic plaque development in mice with and without CD4+ T cells...
June 15, 2017: Circulation Research
https://www.readbyqxmd.com/read/28620067/allele-specific-silencing-of-mutant-mrna-rescues-ultrastructural-and-arrhythmic-phenotype-in-mice-carriers-of-the-r4496c-mutation-in-the-ryanodine-receptor-gene-ryr2
#3
Rossana Bongianino, Marco Denegri, Andrea Mazzanti, Francesco Lodola, Alessandra Vollero, Simona Boncompagni, Silvia Fasciano, Giulia Rizzo, Damiano Mangione, Serena Barbaro, Alessia Di Fonso, Carlo Napolitano, Alberto Auricchio, Feliciano Protasi, Silvia G Priori
Rationale: Mutations in the cardiac Ryanodine Receptor gene (RYR2) cause dominant Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), a leading cause of sudden death in apparently healthy individuals exposed to emotions or physical exercise. Objective: We investigated the efficacy of allele specific silencing by RNA interference to prevent CPVT phenotypical manifestations in our dominant CPVT mice model carriers of the heterozygous mutation R4496C in RYR2Methods and Results: We developed an in vitro mRNA and protein-based assays to screen multiple siRNAs for their ability to selectively silence mutant RYR2-R4496C mRNA over the corresponding wild-type (WT) allele...
June 15, 2017: Circulation Research
https://www.readbyqxmd.com/read/28620066/mitochondrial-complex-iv-subunit-4-isoform-2-is-essential-for-acute-pulmonary-oxygen-sensing
#4
Natascha Sommer, Maik Huttemann, Oleg Pak, Susan Scheibe, Fenja Knöpp, Christopher Sinkler, Monika Malczyk, Mareike Gierhardt, Azadeh Esfandiary, Simone Kraut, Felix T Jonas, Christine Veith, Siddhesh Aras, Akylbek Sydykov, Nasim Alebrahimdehkordi, Klaudia Giehl, Matthias Hecker, Ralf P Brandes, Werner Seeger, Friedrich Grimminger, Hossein A Ghofrani, Ralph T Schermuly, Lawrence I Grossman, Norbert Weissmann
Rationale: Acute pulmonary oxygen sensing is essential to avoid life-threatening hypoxemia via hypoxic pulmonary vasoconstriction (HPV) which matches perfusion to ventilation. Hypoxia-induced mitochondrial superoxide release has been suggested as critical step in the signaling pathway underlying HPV. However, the identity of the primary oxygen sensor and mechanism of superoxide release in acute hypoxia, as well as its relevance for chronic pulmonary oxygen sensing remains unresolved. Objective: To investigate the role of the pulmonary specific isoform 2 of subunit 4 of mitochondrial complex IV (Cox4i2) and the subsequent mediators superoxide and hydrogen peroxide for pulmonary oxygen sensing and signaling...
June 15, 2017: Circulation Research
https://www.readbyqxmd.com/read/28611076/learning-a-comorbidity-driven-taxonomy-of-pediatric-pulmonary-hypertension
#5
Mei-Sing Ong, Mary P Mullen, Eric D Austin, Peter Szolovits, Marc Natter, Alon Geva, Tianxi Cai, Sek Won Kong, Kenneth D Mandl
Rationale: Pediatric pulmonary hypertension (PH) is a heterogeneous condition with varying natural history and therapeutic response. Precise classification of PH subtypes is therefore crucial for individualizing care. However, gaps remain in our understanding of the spectrum of PH in children. Objective: We seek to study the manifestations of PH in children, and to assess the feasibility of applying a network-based approach to discern disease subtypes from comorbidity data recorded in longitudinal datasets...
June 13, 2017: Circulation Research
https://www.readbyqxmd.com/read/28611075/identification-and-functional-characterization-of-hypoxia-induced-endoplasmic-reticulum-stress-regulating-lncrna-hyperlnc-in-pericytes
#6
Florian C Bischoff, Astrid Werner, David John, Jes-Niels Boeckel, Maria-Theodora Melissari, Phillip Grote, Simone F Glaser, Shemsi Demolli, Shizuka Uchida, Katharina M Michalik, Benjamin Meder, Hugo A Katus, Jan Haas, Wei Chen, Soni S Pullamsetti, Werner Seeger, Andreas M Zeiher, Stefanie Dimmeler, Christoph M Zehendner
Rationale: Pericytes are essential for vessel maturation and endothelial barrier function. Long non-coding RNAs (lncRNAs) regulate many cellular functions, but their role in pericyte biology remains unexplored. Objective: Here we investigate the effect of Hypoxia-Induced Endoplasmic Reticulum Stress Regulating lncRNA (HypERlnc, also known as ENSG00000262454) on pericyte function in vitro and its regulation in human heart failure and idiopathic pulmonary arterial hypertension. Methods and Results: RNA sequencing in human primary pericytes (hPCs) identified hypoxia regulated lncRNAs, including HypERlnc...
June 13, 2017: Circulation Research
https://www.readbyqxmd.com/read/28607103/dynamin-related-protein-1-inhibition-attenuates-cardiovascular-calcification-in-the-presence-of-oxidative-stress
#7
Maximillian Rogers, Natalia Maldonado-Martinez, Joshua D Hutcheson, Claudia Goettsch, Shinji Goto, Iwao Yamada, Tyler Faits, Hiromi Sesaki, Masanori Aikawa, Elena Aikawa
Rationale: Mitochondrial changes occur during cell differentiation and cardiovascular disease. Dynamin-related protein 1 (DRP1) is a key regulator of mitochondrial fission. We hypothesized that DRP1 plays a role in cardiovascular calcification, a process involving cell differentiation and a major clinical problem with high unmet needs. Objective: To examine the effects of osteogenic promoting conditions on DRP1, and whether DRP1 inhibition alters the development of cardiovascular calcification. Methods and Results: DRP1 was enriched in calcified regions of human carotid arteries, examined by immunohistochemistry...
June 12, 2017: Circulation Research
https://www.readbyqxmd.com/read/28607102/the-dendritic-cell-receptor-dngr-1-promotes-the-development-of-atherosclerosis-in-mice
#8
Yacine Haddad, Charlotte Lahoute, Marc Clément, Ludivine Laurans, Sarvenaz Metghalchi, Lynda Zeboudj, Andreas Giraud, Xavier Loyer, Marie Vandestienne, Julien Wain-Hobson, Bruno Esposito, Stephane Potteaux, Hafid Ait-Oufella, Alain Tedgui, Ziad Mallat, Soraya Taleb
Rationale: Necrotic core formation during the development of atherosclerosis is associated with a chronic inflammatory response and promotes accelerated plaque development and instability. However, the molecular links between necrosis and the development of atherosclerosis are not completely understood. C-type lectin receptor (Clec9a) or DNGR1 is preferentially expressed by the CD8α(+) subset of dendritic cells (CD8α(+)DCs) and is involved in sensing necrotic cells. We hypothesized that sensing of necrotic cells by DNGR1 plays a determinant role in the inflammatory response of atherosclerosis...
June 12, 2017: Circulation Research
https://www.readbyqxmd.com/read/28596216/effect-of-ischemia-duration-and-protective-interventions-on-the-temporal-dynamics-of-tissue-composition-after-myocardial-infarction
#9
Rodrigo Fernández-Jiménez, Carlos Galan-Arriola, Javier Sanchez-Gonzalez, Jaume Aguero, Gonzalo Lopez-Martin, Sandra Gomez-Talavera, Jaime Garcia-Prieto, Austin Benn, Antonio de Molina, Manuel Barreiro-Perez, Ana Martin-Garcia, Ines Garcia-Lunar, Gonzalo Pizarro, Javier Sanz, Pedro Sánchez, Valentin Fuster, Borja Ibanez
Rationale: The impact of cardioprotective strategies and ischemia duration on post ischemia/reperfusion (I/R) myocardial tissue composition (edema, myocardium at risk [MaR], infarct size [IS], salvage, intramyocardial hemorrhage [IMH] and microvascular obstruction [MVO]) is not well understood. Objective: To study the effect of ischemia duration and protective interventions on the temporal dynamics of myocardial tissue composition in a translational animal model of I/R by the use of state-of-the-art imaging technology...
June 8, 2017: Circulation Research
https://www.readbyqxmd.com/read/28592415/role-of-stim1-in-hypertrophy-related-contractile-dysfunction
#10
Constantine D Troupes, Markus Wallner, Giulia Borghetti, Chen Zhang, Sadia Mohsin, Dirk von Lewinski, Remus M Berretta, Hajime Kubo, Xiongwen Chen, Jonathan Soboloff, Steven R 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. Stromal Interaction Molecule 1 (STIM1) 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 are not well understood...
June 7, 2017: Circulation Research
https://www.readbyqxmd.com/read/28588038/the-amp-related-kinase-ampk-induces-ca-2-independent-dilation-of-resistance-arteries-by-interfering-with-actin-filament-formation
#11
Kai M Schubert, Jiehua Qiu, Stephanie Blodow, Margarethe Wiedenmann, Lubomir T Lubomirov, Gabriele Pfitzer, Ulrich Pohl, Holger Schneider
Rationale: Decreasing Ca(2+) sensitivity of vascular smooth muscle (VSM) allows for vasodilation without lowering of cytosolic Ca(2+) This may be particularly important in states requiring maintained dilation such as hypoxia. AMPK is an important cellular energy sensor in VSM. Regulation of Ca(2+) sensitivity usually is attributed to myosin light chain phosphatase (MLCP) activity but findings in non-VSM identified changes in the actin cytoskeleton. The potential role of AMPK in this setting is widely unknown...
June 6, 2017: Circulation Research
https://www.readbyqxmd.com/read/28584062/cytochrome-b5-reductase-3-modulates-soluble-guanylate-cyclase-redox-state-and-cgmp-signaling
#12
Mizanur M Rahaman, Anh T Nguyen, Megan P Miller, Scott A Hahn, Courtney Sparacino-Watkins, Soma Jobbagy, Nolan T Carew, Nadiezhda Cantu-Medellin, Katherine C Wood, Catherine Baty, Francisco J Schopfer, Eric E Kelley, Mark T Gladwin, Emil Martin, Adam C Straub
Rationale: Soluble guanylate cyclase (sGC) heme iron, in its oxidized state (Fe(3+)), is desensitized to nitric oxide (NO) and limits cyclic guanosine 3', 5'-monophosphate (cGMP) production needed for downstream activation of PKG-dependent signaling and blood vessel dilation. Objective: While reactive oxygen species are known to oxidize the sGC heme iron, the basic mechanism(s) governing sGC heme iron recycling to its NO-sensitive, reduced state, remain poorly understood. Methods and Results: Oxidant challenge studies show vascular smooth muscle cells have an intrinsic ability to reduce oxidized sGC heme iron and form protein-protein complexes between cytochrome b5 reductase 3 (Cyb5R3), also known as methemoglobin reductase, and oxidized sGC...
June 5, 2017: Circulation Research
https://www.readbyqxmd.com/read/28533209/rationale-and-design-of-a-clinical-trial-to-evaluate-the-safety-and-efficacy-of-intracoronary-infusion-of-allogeneic-human-cardiac-stem-cells-in-patients-with-acute-myocardial-infarction-and-left-ventricular-dysfunction-the-randomized-multicenter-double-blind
#13
Ricardo Sanz-Ruiz, Ana Casado Plasencia, Luis R Borlado, María Eugenia Fernández-Santos, Reem Al-Daccak, Piet Claus, Itziar Palacios, Rafael Sádaba, Dominique Charron, Jan Bogaert, Miguel Mulet, Raquel Yotti, Inmaculada Gilaberte, Antonio Bernad, Javier Bermejo, Stefan Janssens, Francisco Fernández-Avilés
Rationale: Stem cell therapy has increased the therapeutic armamentarium in the fight against ischemic heart disease and heart failure (HF). The administration of exogenous stem cells has been investigated in patients suffering an acute myocardial infarction (AMI) with the final aim of salvaging jeopardized myocardium and preventing left ventricular adverse remodeling and functional deterioration. However, phase I and II clinical trials with autologous and "first-generation" stem cells have yielded inconsistent benefits and mixed results...
May 22, 2017: Circulation Research
https://www.readbyqxmd.com/read/28522438/anti-inflammatory-effects-of-oxpapc-involve-endothelial-cell-mediated-generation-of-lxa4
#14
Yunbo Ke, Noureddine Zebda, Olga Oskokova, Taras Afonyushkin, Evgeny Berdyshev, Yufeng Tian, Fanyong Meng, Nicolene Sarich, Valery N Bochkov, Ji Ming Wang, Anna A Birukova, Konstantin G Birukov
Rationale: Oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine generates a group of bioactive oxidized phospholipid products (OxPAPC) with a broad range of biological activities. Barrier-enhancing and anti-inflammatory effects of OxPAPC on pulmonary endothelial cells (EC) are critical for prevention of acute lung injury caused by bacterial pathogens or excessive mechanical ventilation. Anti-inflammatory properties of OxPAPC are associated with its antagonistic effects on toll-like receptors and suppression of RhoA GTPase signaling...
May 18, 2017: Circulation Research
https://www.readbyqxmd.com/read/28515044/exploring-the-causal-pathway-from-telomere-length-to-coronary-heart-disease-a-network-mendelian-randomization-study
#15
Yiqiang Zhan, Ida K Karlsson, Robert Karlsson, Annika Tillander, Chandra A Reynolds, Nancy L Pedersen, Sara Hägg
Rationale: Observational studies have found shorter leukocyte telomere length to be a risk factor for coronary heart disease (CHD), and more recently the association was suggested to be causal. However, the relationship between telomere length and common metabolic risk factors for CHD is not well understood. Whether these risk factors could explain pathways from telomere length to CHD warrants further attention. Objective: To examine if metabolic risk factors for CHD mediate the causal pathway from short telomere length to increased risk of CHD using a network Mendelian randomization (MR) design...
May 17, 2017: Circulation Research
https://www.readbyqxmd.com/read/28515043/brain-perivascular-macrophages-initiate-the-neurovascular-dysfunction-of-alzheimer-a%C3%AE-peptides
#16
Laibaik Park, Ken Uekawa, Lidia Garcia-Bonilla, Kenzo Koizumi, Michelle Murphy, Rose Pitstick, Linda H Younkin, Steven G Younkin, Ping Zhou, Geroge A Carlson, Josef Anrather, Costantino Iadecola
Rationale: Increasing evidence indicates that alterations of the cerebral microcirculation may play a role in Alzheimer's disease (AD), the leading cause of late-life dementia. The amyloid-β peptide (Aβ), a key pathogenic factor in AD, induces profound alterations in neurovascular regulation through the innate immunity receptor CD36, which, in turn, activates a Nox2-containing NADPH oxidase leading to cerebrovascular oxidative stress. Brain perivascular macrophages (PVM) located in the perivascular space, a major site of brain Aβ collection and clearance, are juxtaposed to the wall of intracerebral resistance vessels and are a powerful source of reactive oxygen species (ROS)...
May 17, 2017: Circulation Research
https://www.readbyqxmd.com/read/28512108/clinical-relevance-and-role-of-neuronal-at1-receptors-in-adam17-mediated-ace2-shedding-in-neurogenic-hypertension
#17
Jiaxi Xu, Srinivas Sriramula, Huijing Xia, Lisa Moreno-Walton, Frank Culicchia, Oliver Domenig, Marko Poglitsch, Eric Lazartigues
Rationale: Neurogenic hypertension is characterized by an increase in sympathetic activity and often resistance to drug treatments. We previously reported that it is also associated with a reduction of Angiotensin Converting Enzyme 2 (ACE2) and an increase in A Disintegrin And Metalloprotease 17 (ADAM17) activity in experimental hypertension. In addition, while multiple cells within the central nervous system have been involved in the development of neurogenic hypertension, the contribution of ADAM17 has not been investigated...
May 16, 2017: Circulation Research
https://www.readbyqxmd.com/read/28512107/divergent-requirements-for-ezh1-in-heart-development-versus-regeneration
#18
Shanshan Ai, Xianhong Yu, Yumei Li, Yong Peng, Chen Li, Yanzhu Yue, Ge Tao, Chuan-Yun Li, William T Pu, Aibin He
Rationale: Polycomb repressive complex 2 (PRC2) is a major epigenetic repressor that deposits methylation on histone H3 on lysine 27 (H3K27me) and controls differentiation and function of many cells, including cardiac myocytes. EZH1 and EZH2 are two alternative catalytic subunits with partial functional redundancy. The relative roles of EZH1 and EZH2 in heart development and regeneration are unknown. Objective: We compared the roles of EZH1 versus EZH2 in heart development and neonatal heart regeneration. Methods and Results: Heart development was normal in Ezh1(-/-) (E1KO) and Ezh2(f/f)::cTNT(-Cre) (E2KO) embryos...
May 16, 2017: Circulation Research
https://www.readbyqxmd.com/read/28506971/protein-truncating-variants-at-the-cholesteryl-ester-transfer-protein-gene-and-risk-for-coronary-heart-disease
#19
Akihiro Nomura, Hong-Hee Won, Amit V Khera, Fumihiko Takeuchi, Kaoru Ito, Shane McCarthy, Connor A Emdin, Derek Klarin, Pradeep Natarajan, Seyedeh M Zekavat, Namrata Gupta, Gina M Peloso, Ingrid B Borecki, Tanya M Teslovich, Rosanna Asselta, Stefano Duga, Piera A Merlini, Adolfo Correa, Thorsten Kessler, James G Wilson, Matthew J Bown, Alistair S Hall, Peter S Braund, David J Carey, Michael F Murray, H L Kirchner, Joseph B Leader, Daniel R Lavage, J N Manus, Dustin N Hartzel, Nilesh J Samani, Heribert Schunkert, Jaume Marrugat, Roberto Elosua, Ruth McPherson, Martin Farrall, Hugh Watkins, Jyh-Ming Jimmy Juang, Chao A Hsiung, Shih-Yi Lin, Jun-Sing Wang, Hayato Tada, Masa-Aki Kawashiri, Akihiro Inazu, Masakazu Yamagishi, Tomohiro Katsuya, Eitaro Nakashima, Masahiro Nakatochi, Ken Yamamoto, Mitsuhiro Yokota, Yukihide Momozawa, Jerome I Rotter, Eric S Lander, Daniel J Rader, John N Danesh, Diego Ardissino, Stacey B Gabriel, Cristen J Willer, Gonçalo Abecasis, Danish Saleheen, Michiaki Kubo, Norihiro Kato, Yii-Der I Chen, Frederick Dewey, Sekar Kathiresan
Rationale: Therapies which inhibit cholesteryl ester transfer protein (CETP) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human deoxyribonucleic acid sequence variants that truncate the CETP gene may provide insight into the efficacy of CETP inhibition. Objective: To test whether protein truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD. Methods and Results: We sequenced the exons of the CETP gene in 58,469 participants from 12 case-control studies (18,817 CHD cases, 39,652 CHD-free controls)...
May 15, 2017: Circulation Research
https://www.readbyqxmd.com/read/28490433/peripheral-blood-cytokine-levels-after-acute-myocardial-infarction-il-1%C3%AE-and-il-6-related-impairment-of-bone-marrow-function
#20
Mahan Shahrivari, Elizabeth Wise, Micheline M Resende, Jonathan J Shuster, Jingnan Zhang, Roberto Bolli, John P Cooke, Joshua M Hare, Timothy D Henry, Aisha Khan, Doris A Taylor, Jay H Traverse, Phillip C Yang, Carl J Pepine, Christopher R Cogle
Rationale: Intracoronary infusion of bone marrow mononuclear cells (BM-MNCs) after acute myocardial infarction (AMI) has led to limited improvement in left ventricular (LV) function. Although experimental AMI models have implicated cytokine-related impairment of progenitor cell function, this response has not been investigated in humans. Objective: To test the hypothesis that peripheral blood (PB) cytokines predict bone marrow (BM) endothelial progenitor cell (EPC) colony outgrowth and cardiac function after AMI...
May 10, 2017: Circulation Research
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