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Circulation Research

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https://www.readbyqxmd.com/read/28325782/aibp-limits-angiogenesis-thorough-%C3%AE-secretase-mediated-upregulation-of-notch-signaling
#1
Renfang Mao, Shu Meng, Qilin Gu, Raquel Araujo-Gutierrez, Sandeep Kumar, Qing Yan, Felicidad Almazan, Keith A Youker, Yingbin Fu, Henry J Pownall, John P Cooke, Yury I Miller, Longhou Fang
Rationale: Angiogenesis improves perfusion to the ischemic tissue following acute vascular obstruction. Angiogenesis in pathophysiological settings reactivates signaling pathways involved in developmental angiogenesis. We showed previously that apoA-I binding protein (AIBP)-regulated cholesterol efflux in endothelial cells (ECs) controls zebrafish embryonic angiogenesis. Objective: This study is to determine whether loss of AIBP affects angiogenesis in mice during development and under pathological conditions, and to explore the underlying molecular mechanism...
March 21, 2017: Circulation Research
https://www.readbyqxmd.com/read/28325781/hete-signals-through-g-protein-coupled-receptor-gpr75-gq-to-affect-vascular-function-and-trigger-hypertension
#2
Victor Garcia, Ankit Gilani, Brian Shkolnik, Varunkumar Pandey, Frank F Zhang, Rambabu Dakarapu, Shyam K Gandham, N R Reddy, Joan P Graves, Artiom Gruzdev, Darryl C Zeldin, Jorge H Capdevila, John R Falck, Michal L Schwartzman
Rationale: 20-Hydroxyeicosatetraenoic acid (20-HETE), one of the principle cytochrome P450 (CYP) eicosanoids, is a potent vasoactive lipid whose vascular effects include stimulation of smooth muscle contractility, migration and proliferation, as well as endothelial cell dysfunction and inflammation. Increased levels of 20-HETE in experimental animals and in humans are associated with hypertension, stroke, myocardial infarction and vascular diseases. Objective: To date, a receptor/binding site for 20-HETE has been implicated based on the use of specific agonists and antagonists...
March 21, 2017: Circulation Research
https://www.readbyqxmd.com/read/28302649/endothelial-protective-monocyte-patrolling-in-large-arteries-intensified-by-western-diet-and-atherosclerosis
#3
Amado Quintar, Sara McArdle, Dennis Wolf, Alex Marki, Erik Ehinger, Melanie Vassallo, Jacqueline F Miller, Zbigniew Mikulski, Klaus Ley, Konrad Buscher
Rationale: Non-classical mouse monocyte (CX3CR1(high), Ly-6C(low)) patrolling along the vessels of the microcirculation is critical for endothelial homeostasis and inflammation. Due to technical challenges it is currently not established how patrolling occurs in large arteries. Objective: This study was undertaken to elucidate the molecular, migratory and functional phenotype of patrolling monocytes in the high shear and pulsatile environment of large arteries in healthy, hyperlipidemic and atherosclerotic conditions...
March 16, 2017: Circulation Research
https://www.readbyqxmd.com/read/28298297/angiogenic-mechanisms-of-human-cd34-stem-cell-exosomes-in-the-repair-of-ischemic-hindlimb
#4
Prabhu Mathiyalagan, Yaxuan Liang, David Kim, Sol Misener, Tina Thorne, Christine Kamide, Ekaterina Klyachko, Douglas W Losordo, Roger J Hajjar, Susmita Sahoo
Rationale: Paracrine secretions appear to mediate therapeutic effects of human CD34(+) stem cells locally transplanted in patients with myocardial and critical limb ischemia as well as in animal models. Earlier, we had discovered that paracrine secretion from human CD34(+) cells contains pro-angiogenic, membrane-bound nano-vesicles called exosomes (CD34Exo). Objective: Here, we investigated the mechanisms of CD34Exo-mediated ischemic tissue repair and therapeutic angiogenesis by studying their miRNA content and uptake...
March 15, 2017: Circulation Research
https://www.readbyqxmd.com/read/28298296/fabrication-of-synthetic-mesenchymal-stem-cells-for-the-treatment-of-acute-myocardial-infarction-in-mice
#5
Lan Luo, Junnan Tang, Kodai Nishi, Chen Yan, Phuong-Uyen Dinh, Jhon Cores, Takashi Kudo, Jinying Zhang, Tao-Sheng Li, Ke Cheng
Rationale: Stem cell therapy faces a number of challenges. It is difficult to grow, preserve, and transport stem cells before they are administered to the patient. Synthetic analogs for stem cells represent a new approach to overcome these hurdles and hold the potential to revolutionize regenerative medicine. Objective: We aim to fabricate synthetic analogs of stem cells and test their therapeutic potential for treatment of acute myocardial infarction in mice. Methods and Results: We packaged secreted factors from human bone marrow-derived mesenchymal stem cells (MSC) into Poly(lactic-co-glycolic acid) PLGA microparticles and then coated them with MSC membranes...
March 15, 2017: Circulation Research
https://www.readbyqxmd.com/read/28298295/t-cell-mineralocorticoid-receptor-controls-blood-pressure-by-regulating-interferon-gamma
#6
Xue Nan Sun, Chao Li, Yuan Liu, Lin-Juan Du, Meng-Ru Zeng, Xiao Jun Zheng, Wu Chang Zhang, Yan Liu, Mingjiang Zhu, Deping Kong, Li Zhou, Limin Lu, Zhu-Xia Shen, Yi Yi, Lili Du, Mu Qin, Xu Liu, Zichun Hua, Shuyang Sun, Huiyong Yin, Bin Zhou, Ying Yu, Zhiyuan Zhang, Sheng-Zhong Duan
Rationale: Hypertension remains to be a global public health burden and demands novel intervention strategies such as targeting T cells and T cell-derived cytokines. Mineralocorticoid receptor (MR) antagonists have been clinically used to treat hypertension. However, the function of T cell MR in blood pressure (BP) regulation has not been elucidated. Objective: We aim to determine the role of T cell MR in BP regulation and to explore the mechanism. Methods and Results: Using T cell MR knockout (TMRKO) mouse in combination with angiotensin II (AngII)-induced hypertensive mouse model, we demonstrated that MR deficiency in T cells strikingly decreased both systolic and diastolic BP, and attenuated renal and vascular damage...
March 15, 2017: Circulation Research
https://www.readbyqxmd.com/read/28298294/vegfr3-modulates-vascular-permeability-by-controlling-vegf-vegfr2-signaling
#7
Krista Heinolainen, Sinem Karaman, Gabriela D'Amico, Tuomas Tammela, Raija Sormunen, Lauri Eklund, Kari Alitalo, Georgia Zarkada
Rationale: Vascular endothelial growth factor (VEGF) is the main driver of angiogenesis and vascular permeability via VEGF receptor 2 (VEGFR2), while lymphangiogenesis signals are transduced by VEGFC/D via VEGFR3. VEGFR3 also regulates sprouting angiogenesis and blood vessel growth, but to what extent VEGFR3 signaling controls blood vessel permeability remains unknown. Objective: To investigate the role of VEGFR3 in the regulation of VEGF-induced vascular permeability. Methods and Results: Long-term global Vegfr3 gene deletion in adult mice resulted in increased fibrinogen deposition in lungs and kidneys, indicating enhanced vascular leakage at the steady state...
March 15, 2017: Circulation Research
https://www.readbyqxmd.com/read/28289018/adrenergic-signaling-strengthens-cardiac-myocyte-cohesion
#8
Camilla Schinner, Franziska Vielmuth, Vera Rötzer, Matthias Hiermaier, Mariya Radeva, Thu K Co, Eva Hartlieb, Andreas Schmidt, Axel Imhof, Ahmed Messoudi, Anja Horn, Angela Schlipp, Volker Spindler, Jens Waschke
Rationale: The sympathetic nervous system is a major mediator of heart function. Intercalated discs (ICDs) composed of desmosomes, adherens junctions and gap junctions provide the structural backbone for coordinated contraction of cardiac myocytes. Objective: Gap junctions dynamically remodel to adapt to sympathetic signaling. However, it is unknown whether such rapid adaption also occurs for the adhesive function provided by desmosomes and adherens junctions. Methods and Results: Atomic force microscopy revealed that β-adrenergic signaling enhances both the number of desmoglein 2 (Dsg2) -specific interactions along cell junctions and the mean Dsg2-mediated binding forces, whereas N-cadherin-mediated interactions were not affected...
March 13, 2017: Circulation Research
https://www.readbyqxmd.com/read/28289017/activated-tafi-promotes-the-development-of-chronic-thromboembolic-pulmonary-hypertension-a-possible-novel-therapeutic-target
#9
Taijyu Satoh, Kimio Satoh, Nobuhiro Yaoita, Nobuhiro Kikuchi, Junichi Omura, Ryo Kurosawa, Kazuhiko Numano, Elias Al-Mamun, Mohammad Abdul Hai Siddique, Shinichiro Sunamura, Masamichi Nogi, Kota Suzuki, Satoshi Miyata, John Morser, Hiroaki Shimokawa
Rationale: Pulmonary hypertension (PH) is a fatal disease; however, its pathogenesis still remains to be elucidated. Thrombin-activatable fibrinolysis inhibitor (TAFI) is synthesized by the liver and inhibits fibrinolysis. Plasma TAFI levels are significantly increased in chronic thromboembolic PH (CTEPH) patients. Objective: To determine the role of activated TAFI (TAFIa) in the development of CTEPH. Methods and Results: Immunostaining showed that TAFI and its binding partner thrombomodulin (TM) were highly expressed in the pulmonary arteries (PA) and thrombus in patients with CTEPH...
March 13, 2017: Circulation Research
https://www.readbyqxmd.com/read/28264867/a-new-approach-to-pcsk9-therapeutics
#10
Nan Wang, Alan R Tall
PCSK9 inhibition is an effective therapy to reduce LDL cholesterol (LDL-C) and cardiovascular events. A recent study shows that one or two doses of inclisiran, a long-acting synthetic small-interfering RNA (siRNA) that selectively targets hepatic PCSK9, causes a sustained reduction of plasma LDL-C for up to 6 months. Pending further studies of safety and efficacy, this may represent an important addition to the armamentarium for inhibiting PCSK9.
March 6, 2017: Circulation Research
https://www.readbyqxmd.com/read/28246128/a-comprehensive-talen-based-knockout-library-for-generating-human-induced-pluripotent-stem-cell-based-models-for-cardiovascular-diseases
#11
Ioannis Karakikes, Vittavat Termglinchan, Diana A Cepeda, Jaecheol Lee, Sebastian Diecke, Ayal Hendel, Ilanit Itzhaki, Mohamed Ameen, Rajani Shrestha, Haodi Wu, Ning Ma, Ning-Yi Shao, Timon Seeger, Nicole A Woo, Kitchener D Wilson, Elena Matsa, Matthew H Porteus, Vittorio Sebastiano, Joseph C Wu
Rationale: Targeted genetic engineering using programmable nucleases such as transcription activator-like effector nucleases (TALENs) is a valuable tool for precise, site-specific genetic modification in the human genome. Objective: The emergence of novel technologies such as human induced pluripotent stem cells (iPSCs) and nuclease-mediated genome editing represent a unique opportunity for studying cardiovascular diseases in vitro. Methods and Results: By incorporating extensive literature and database searches, we designed a collection of TALEN constructs to knockout (KO) eighty-eight human genes that are associated with cardiomyopathies and congenital heart diseases...
February 28, 2017: Circulation Research
https://www.readbyqxmd.com/read/28232595/intravenously-delivered-mesenchymal-stem-cells-systemic-anti-inflammatory-effects-improve-left-ventricular-dysfunction-in-acute-myocardial-infarction-and-ischemic-cardiomyopathy
#12
Dror Luger, Michael J Lipinski, Peter C Westman, David K Glover, Julien Dimastromatteo, Juan C Frias, M T Albelda, Sergey Sikora, Alex Kharazi, Grigory Vertelov, Ron Waksman, Stephen E Epstein
Rationale: Virtually all mesenchymal stem cell (MSC) studies assume therapeutic effects accrue from local myocardial effects of engrafted MSCs. Since few intravenously-administered MSCs engraft in the myocardium, studies have mainly utilized direct myocardial delivery. We adopted a different paradigm. Objective: To test whether intravenously-administered MSCs reduce LV dysfunction both post-AMI and in ischemic cardiomyopathy, and that these effects are caused, at least partly, by systemic anti-inflammatory activities...
February 23, 2017: Circulation Research
https://www.readbyqxmd.com/read/28232594/long-term-excessive-body-weight-and-adult-left-ventricular-hypertrophy-are-linked-through-later-life-body-size-and-blood-pressure-the-bogalusa-heart-study
#13
Huijie Zhang, Tao Zhang, Shengxu Li, Yajun Guo, Wei Shen, Camilo Fernandez, Emily W Harville, Lydia A Bazzano, Elaine M Urbina, Jiang He, Wei Chen
Rationale: Childhood adiposity is associated with cardiac structure in later life, but little is known regarding to what extent childhood body weight affects adult left ventricular geometric patterns through adult body size and blood pressure (BP). Objective: Determine quantitatively the mediation effect of adult body weight and BP on the association of childhood BMI with adult left ventricular hypertrophy (LVH). Methods and Results: This longitudinal study consisted of 710 adults, age 26 to 48 years, who had been examined for BMI and BP measured 4 or more times during childhood and 2 or more times during adulthood, with a mean follow-up period of 28...
February 23, 2017: Circulation Research
https://www.readbyqxmd.com/read/28223422/a-potential-oligogenic-etiology-of-hypertrophic-cardiomyopathy-a-classic-single-gene-disorder
#14
Lili Li, Matthew N Bainbridge, Yanli Tan, James T Willerson, Ali J Marian
Rationale: Hypertrophic cardiomyopathy (HCM) is a prototypic single gene disease caused mainly by mutations in genes encoding sarcomere proteins. Despite the remarkable advances, the causal genes in about 40% of the HCM cases remain unknown, typically in small families and sporadic cases, wherein co-segregation could not be established. Objective: To test the hypothesis that the "missing causal genes" in HCM is, in part, because of an oligogenic etiology, wherein the pathogenic variants do not co-segregate with the phenotype...
February 21, 2017: Circulation Research
https://www.readbyqxmd.com/read/28219978/a-mutation-in-the-g-protein-gene-gnb2-causes-familial-sinus-node-and-atrioventricular-conduction-dysfunction
#15
Birgit Stallmeyer, Johanna Kuß, Stefan Kotthoff, Sven Zumhagen, Kirsty S Vowinkel, Susanne Rinne, Lina A Matschke, Corinna Friedrich, Ellen Schulze-Bahr, Stephan Rust, Guiscard Seebohm, Niels Decher, Eric Schulze-Bahr
Rationale: Familial sinus node and atrioventricular (AV) conduction dysfunction is a rare disorder that leads to paroxysmal dizziness, fatigue and syncope due to a temporarily or permanent reduced heart rate. To date, only a few genes for familial sinus and/or AV conduction dysfunction are known and the majority of cases remain etiologically unresolved. Objective: We aim to identify the disease gene in a large three-generation family (n=25) with autosomal dominant sinus node dysfunction (SND) and AV block (AVB) and to characterise the mutation-related pathomechanisms in familial SND+AVB...
February 20, 2017: Circulation Research
https://www.readbyqxmd.com/read/28219977/adrenergic-receptors-in-individual-ventricular-myocytes-the-beta-1-and-alpha-1b-are-in-all-cells-the-alpha-1a-is-in-a-subpopulation-and-the-beta-2-and-beta-3-are-mostly-absent
#16
Bat-Erdene Myagmar, James M Flynn, Patrick M Cowley, Philip Swigart, Megan Montgomery, Kevin Thai, Divya R Nair, Rumita Gupta, Chihiro Hosoda, Simon Melov, Anthony J Baker, Paul C Simpson
Rationale: It is unknown if every ventricular myocyte expresses all 5 of the cardiac adrenergic receptors (ARs), beta-1, beta-2, beta-3, alpha-1A, and alpha-1B. The beta-1 and beta-2 are thought to be the dominant myocyte ARs. Objective: Quantify the 5 cardiac ARs in individual ventricular myocytes. Methods and Results: We studied ventricular myocytes from wild type mice, mice with alpha-1A and alpha-1B knockin reporters, and beta-1 and beta-2 knockout mice. Using individual isolated cells, we measured knockin reporters, mRNAs, signaling (phosphorylation of ERK and phospholamban), and contraction...
February 20, 2017: Circulation Research
https://www.readbyqxmd.com/read/28209718/demethylation-of-h3k27-is-essential-for-the-induction-of-direct-cardiac-reprogramming-by-mir-combo
#17
Sophie Dal-Pra, Conrad P Hodgkinson, Maria Mirotsou, Imke Kirste, Victor J Dzau
Rationale: Direct reprogramming of cardiac fibroblasts to cardac omyocytes has recently emerged as a novel and promising approach to regenerate the injured myocardium. We have previously demonstrated the feasibility of this approach in vitro and in vivo using a combination of four microRNAs (miR-1, miR-133, miR-208 and miR-499) that we named miR combo. However, the mechanism of miR combo mediated direct cardiac reprogramming is currently unknown. Objective: Here we investigated the possibility that miR combo initiated direct cardiac reprogramming through an epigenetic mechanism...
February 16, 2017: Circulation Research
https://www.readbyqxmd.com/read/28193608/dectin-2-deficiency-modulates-th1-differentiation-and-improves-wound-healing-after-myocardial-infarction
#18
Xiaoxiang Yan, Hang Zhang, Qin Fan, Jian Hu, Rong Tao, Qiujing Chen, Yoichiro Iwakura, Weifeng Shen, Lin Lu, Qi Zhang, Ruiyan Zhang
Rationale: Macrophages are involved in wound healing after myocardial infarction (MI). The role of Dectin-2, a pattern recognition receptor mainly expressed on myeloid cells, in the infarct healing remains unknown. Objective: To determine whether Dectin-2 signaling is involved in the healing process and cardiac remodeling after MI, and to elucidate the underlying molecular mechanisms. Methods and Results: In a mouse model of permanent coronary ligation, Dectin-2, mainly expressed in macrophages, was shown to be increased in the early phase after MI...
February 13, 2017: Circulation Research
https://www.readbyqxmd.com/read/28179432/an-evolutionarily-conserved-role-for-polydom-svep1-during-lymphatic-vessel-formation
#19
Terhi Kärpanen, Yvonne Padberg, Serge A van de Pavert, Cathrin Dierkes, Nanami Morooka, Josi Peterson-Maduro, Glenn van de Hoek, Max Adrian, Naoki Mochizuki, Kiyotoshi Sekiguchi, Friedemann Kiefer, Dörte Schulte, Stefan Schulte-Merker
Rationale: Lymphatic vessel formation and function constitutes a physiologically and pathophysiologically important process, but its genetic control is not well understood. Objective: Here, we identify the secreted Polydom/Svep1 protein as essential for formation of the lymphatic vasculature. We analyzed mutants in mice and zebrafish to gain insight into the role of Polydom/Svep1 in the lymphangiogenic process. Methods and Results: Phenotypic analysis of zebrafish polydom/svep1 mutants showed a decrease in venous and lympho-venous sprouting, which leads to an increased number of intersegmental arteries...
February 8, 2017: Circulation Research
https://www.readbyqxmd.com/read/28179431/repeated-cell-therapy-a-paradigm-shift-whose-time-has-come
#20
Roberto Bolli
Although treatment with stem/progenitor cells is a promising approach to heart disease, enthusiasm for cell therapy has been dampened by the inconsistent, modest, borderline, or undetectable benefits reported in clinical trials (all of which have used one dose of cells). As a result, clinical translation has not occurred (no cell-based therapy is close to being approved for heart disease), and a rising tide of skepticism has bedeviled the field,leading some critics even to question whether clinical studies should continue...
February 8, 2017: Circulation Research
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