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Circulation Research

Shengbing Wang, Vidya Venkatraman, Erin L Crowgey, Ting Liu, Zongming Fu, Ronald J Holewinski, Mark J J Ranek, David A Kass, Brian O'Rourke, Jennifer E Van Eyk
<u>Rationale:</u> Glycogen synthase kinase 3β (GSK3β) is a multifunctional and constitutively active kinase known to regulate a myriad of cellular processes. The primary mechanism to regulate its function is through phosphorylation-dependent inhibition at serine-9 residue. Emerging evidence indicates that there may be alternative mechanisms that control GSK3β for certain functions. <u>Objective:</u> Here we sought to understand the role of protein S-nitrosylation (SNO) on the function of GSK3β...
March 21, 2018: Circulation Research
Alina Fedoseienko, Melinde Wijers, Justina C Wolters, Daphne Dekker, Marieke Smit, Nicolette Huijkman, Niels Kloosterhuis, Helene Klug, Aloys Schepers, Ko Willems van Dijk, Johannes H Levels, Daniel D Billadeau, Marten H Hofker, Jan van Deursen, Marit Westerterp, Ezra Burstein, Jan Albert Kuivenhoven, Bart van de Sluis
<u>Rationale:</u> <u>CO</u> pper<u>M</u>etabolism<u>M</u>URR1 Domain-containing (COMMD) proteins are a part of the COMMD-CCDC22-CCDC93 (CCC) complexes facilitating endosomal trafficking of cell surface receptors. Hepatic COMMD1 inactivation decreases CCDC22 and CCDC93 protein levels, impairs the recycling of the low-density lipoprotein receptor (LDLR), and increases plasma LDL cholesterol levels in mice. However, whether any of the other COMMD members function similarly as COMMD1, and whether perturbation in the CCC complex promotes atherogenesis remain unclear...
March 15, 2018: Circulation Research
Rasa Tamosiuniene, Olga Manouvakhova, Paul Mesange, Toshie Saito, Jin Qian, Mrinmoy Sanyal, Yu-Chun Lin, Linh P Nguyen, Amir Luria, Allen B Tu, Joshua M Sante, Marlene Rabinovitch, Desmond J Fitzgerald, Brian B Graham, Aida Habtezion, Norbert F Voelkel, Laure Aurelian, Mark R Nicolls
<u>Rationale:</u> Pulmonary arterial hypertension (PH) is a life-threatening condition associated with immune dysregulation and abnormal regulatory T cell (Treg) activity, but it is currently unknown whether and how abnormal Treg function differentially affects males and females. <u>Objective:</u> To evaluate whether and how Treg-deficiency differentially affects male and female rats in experimental PH. <u>Methods and Results:</u> Male and female athymic rnu/rnu rats, lacking Tregs, were treated with the vascular endothelial growth factor receptor-2 (VEGFR2) inhibitor SU5416 or chronic hypoxia and evaluated for PH; some animals underwent Treg immune reconstitution (IR) before SU5416 administration...
March 15, 2018: Circulation Research
Holger Winkels, Erik Ehinger, Melanie Vassallo, Konrad Buscher, Huy Dinh, Kouji Kobiyama, Anouk Hamers, Clément Cochain, Ehsan Vafadarnejad, Antoine-Emmanuel Saliba, Alma Zernecke, Akula Pramod, Amlan Ghosh, Nathaly Anto Michel, Natalie Hoppe, Ingo Hilgendorf, Andreas Zirlik, Catherine Hedrick, Klaus Ley, Dennis Wolf
<u>Rationale:</u> Atherosclerosis is a chronic inflammatory disease that is driven by the interplay of pro- and anti-inflammatory leukocytes in the aorta. Yet, the phenotypic and transcriptional diversity of aortic leukocytes is only poorly understood. <u>Objective:</u> We characterized leukocytes from healthy and atherosclerotic mouse aortas in-depth by single cell RNA-sequencing (scRNAseq) and mass cytometry (CyTOF) to define an atlas of the immune cell landscape in atherosclerosis...
March 15, 2018: Circulation Research
Clément Cochain, Ehsan Vafadarnejad, Panagiota Arampatzi, Pelisek Jaroslav, Holger Winkels, Klaus Ley, Dennis Wolf, Antoine-Emmanuel Saliba, Alma Zernecke
<u>Rationale:</u> It is assumed that atherosclerotic arteries contain several macrophage subsets endowed with specific functions. The precise identity of these subsets is poorly characterized as they ha ve been defined by the expression of a restricted number of markers. <u>Objective:</u> We have applied single-cell RNA-seq as an unbiased profiling strategy to interrogate and classify aortic macrophage heterogeneity at the single-cell level in atherosclerosis. <u>Methods and Results:</u> We performed single-cell RNA sequencing of total aortic CD45+ cells extracted from the non-diseased (chow fed) and atherosclerotic (11 weeks of high fat diet) aorta of Ldlr-/- mice...
March 15, 2018: Circulation Research
Ali J Marian, Yanli Tan, Lili Li, Jeffrey T Chang, Petros Syrris, Manouchehr Hessabi, Mohammad H Rahbar, James T Willerson, Benjamin Y Cheong, Chia-Ying Liu, Neal S Kleiman, David A Bluemke, Sherif F Nagueh
<u>Rationale:</u> Hypertrophic cardiomyopathy (HCM) is a genetic paradigm of cardiac hypertrophy. Cardiac hypertrophy and interstitial fibrosis are important risk factors for sudden death and morbidity in HCM. Oxidative stress is implicated in the pathogenesis of cardiac hypertrophy and fibrosis. Treatment with anti-oxidant N-acetylcysteine (NAC) reverses cardiac hypertrophy and fibrosis in animal models of HCM. <u>Objective:</u> To determine effect sizes of NAC on indices of cardiac hypertrophy and fibrosis in patients with established HCM...
March 14, 2018: Circulation Research
Ying-Chun Shih, Chao-Ling Chen, Yan Zhang, Rebecca L Mellor, Evelyn M Kanter, Yun Fang, Hua-Chi Wang, Chen-Ting Hung, Jing-Yi Nong, Hui-Ju Chen, Tzu-Han Lee, Yi-Shuan Tseng, Chiung-Nien Chen, Chau-Chung Wu, Shuei-Liong Lin, Kathryn A Yamada, Jeanne M Nerbonne, Kai-Chien Yang
<u>Rationale:</u> Cardiac fibrosis plays a critical role in the pathogenesis of heart failure (HF). Excessive accumulation of extracellular matrix (ECM) resulting from cardiac fibrosis impairs cardiac contractile function and increases arrhythmogenicity. Current treatment options for cardiac fibrosis, however, are limited and there is a clear need to identify novel mediators of cardiac fibrosis to facilitate the development of better therapeutics. Exploiting co-expression gene network analysis on RNA sequencing data from failing human heart, we identified thioredoxin domain containing 5 (TXNDC5), a cardiac fibroblast (CF)-enriched endoplasmic reticulum (ER) protein, as a potential novel mediator of cardiac fibrosis and we completed experiments to test this hypothesis directly...
March 13, 2018: Circulation Research
Cristina Menni, Ivan Gudelj, Erin MacDonald-Dunlop, Massimo Mangino, Jonas Zierer, Erim Bešić, Peter Joshi, Irena Trbojević-Akmačić, Phil J Chowienczyk, Timothy D Spector, James F Wilson, Gordan Lauc, Ana M Valdes
<u>Rationale:</u> One measure of protein glycosylation (GlycA) has been reported to predict higher cardiovascular risk by reflecting inflammatory pathways <u>Objective:</u> To assess the role of a comprehensive panel of immunoglobulin (IgG) glycosylation traits on traditional risk factors for cardiovascular disease and on presence of subclinical atherosclerosis in addition to GlycA. <u>Methods and Results:</u> We measured 76 IgG glycosylation traits in 2970 women (age range 40-79 years) from the TwinsUK cohort and correlated it to their estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk score and their carotid and femoral plaque measured by ultrasound imaging...
March 13, 2018: Circulation Research
Manon Viaud, Stoyan Ivanov, Nemanja Vujic, Madalina Duta-Mare, Lazaro-Emilio Aira, Thibault Barouillet, Elsa Garcia, François Orange, Isabelle Dugail, Isabelle Hainault, Christian Stehlik, Sandrine Marchetti, Laurent Boyer, Rodolphe Guinamard, Fabienne Foufelle, Andrea E Bochem, Kees G Hovingh, Edward B Thorp, Emmanuel L Gautier, Dagmar Kratky, Paul A Da Silva-Jardine, Laurent Yvan-Charvet
<u>Rationale:</u> Macrophages face a substantial amount of cholesterol following the ingestion of apoptotic cells and the lysosomal acid lipase (LIPA) has a major role in hydrolyzing cholesteryl esters in the endocytic compartment. <u>Objective:</u> Here, we directly investigated the role of LIPA-mediated clearance of apoptotic cells both in vitro and in vivo. <u>Methods and Results:</u> We show that LIPA inhibition causes a defective efferocytic response due to impaired generation of 25-OHC and 27-OHC...
March 9, 2018: Circulation Research
Daniela Ponce-Balbuena, Guadalupe Guerrero-Serna, Carmen R Valdivia, Ricardo Caballero, F J Díez-Guerra, Eric N Jiménez-Vázquez, Rafael J Ramirez, Andre Monteiro da Rocha, Todd J Herron, Katherine F Campbell, B C Willis, Francisco J Alvarado, Manuel Zarzoso, Kuljeet Kaur, Marta Pérez-Hernández, Marcos Matamoros, Héctor H Valdivia, Eva Delpón, José Jalife
<u>Rationale:</u> In cardiomyocytes, NaV 1.5 and Kir2.1 channels interact dynamically as part of membrane bound macromolecular complexes. <u>Objective:</u> To test whether NaV 1.5 and Kir2.1 preassemble during early forward trafficking and travel together to common membrane microdomains. <u>Methods and Results:</u> In patch-clamp experiments, co-expression of trafficking deficient mutants Kir2.1Δ314-315 or Kir2.1R44A/R46A with wildtype (WT) NaV 1.5WT in heterologous cells reduced INa , compared to NaV 1...
March 7, 2018: Circulation Research
Ayman S Samman Tahhan, Muhammad Hammadah, Mohamad Raad, Zakaria Almuwaqqat, Ayman Alkhoder, Pratik B Sandesara, Heval Kelli, Salim S Hayek, Jeong H Kim, Wesley T O'Neal, Matthew L Topel, Aubrey J Grant, Nabil Sabbak, Robert E Heinl, Mohamad M Gafeer, Malik Obideen, Belal Kaseer, Naser Abdelhadi, Yi-An Ko, Chang Liu, Iraj Ghaini, Ernestine A Mahar, Viola Vaccarino, Edmund K Waller, Arshed A Quyyumi
<u>Rationale:</u> Circulating progenitor cells (CPCs) mobilize in response to ischemic injury, but their predictive value remains unknown in acute coronary syndrome (ACS). <u>Objective:</u> We aimed to investigate the number of CPCs in ACS compared to those with stable coronary artery disease (CAD), relationship between bone marrow PCs and CPCs, and whether CPC counts predict mortality in patients with ACS. <u>Methods and Results:</u> In 2028 patients, 346 had unstable angina, 183 had an acute myocardial infarction (AMI) and the remaining 1499 patients had stable CAD...
March 7, 2018: Circulation Research
Peter P Rainer, Peihong Dong, Matteo Sorge, Justyna Fert-Bober, Ronald J Holewinski, Yuchuan Wang, Catherine Foss, Steven S An, Alessandra Baracca, Giancarlo Solaini, Charles Glabe, Martin G Pomper, Jennifer E Van Eyk, Gordon F Tomaselli, Nazareno Paolocci, Giulio Agnetti
<u>Rationale:</u> Disrupted proteostasis is one major pathological trait that heart failure (HF) shares with other organ proteinopathies, such as Alzheimer's and Parkinson's diseases. Yet, differently from the latter, whether and how cardiac preamyloid oligomers (PAOs) develop in acquired forms of HF is unclear. <u>Objective:</u> We previously reported a rise in mono-phosphorylated, aggregate-prone desmin in canine and human HF. We now tested if mono-phosphorylated desmin acts as the seed nucleating PAOs formation and determined if positron emission tomography (PET) is able to detect myocardial PAOs in non-genetic HF...
February 26, 2018: Circulation Research
Mohammed R Hosen, Giuseppe Militello, Tyler M Weirick, Yuliya Ponomareva, Sujith Dassanayaka, Joseph B Moore, Claudia Doering, Marcin Wysoczynski, Steven P Jones, Stefanie Dimmeler, Shizuka Uchida
<u>Rationale:</u> Increasing evidence indicates the presence of long noncoding RNAs (lncRNAs) in various cell types. Airn is an imprinting gene transcribed from the paternal chromosome. It is in antisense orientation to the imprinted, but maternally-derived, Igf2r gene, on which Airn exerts its regulation in cis Although Airn is highly expressed in the heart, functions aside from imprinting remain unknown. <u>Objective:</u> Here, we studied the functions of Airn in the heart, especially cardiomyocytes...
February 26, 2018: Circulation Research
Yoshihisa Yamada, Shohei Wakao, Yoshihiro Kushida, Shingo Minatoguchi, Atsushi Mikami, Kenshi Higashi, Shinya Baba, Taeko Shigemoto, Yasumasa Kuroda, Hiromitsu Kanamori, Mohamad Amin, Masanori Kawasaki, Kazuhiko Nishigaki, Masato Taoka, Toshiaki Isobe, Chisako Muramatsu, Mari Dezawa, Shinya Minatoguchi
<u>Rationale:</u> Muse cells, pluripotent marker SSEA-3+ cells, are non-tumorigenic endogenous pluripotent-like stem cells obtainable from various tissues including the bone marrow (BM). Their therapeutic efficiency has not been validated in the acute myocardial infarction (AMI). <u>Objective:</u> To clarify the efficiency of intravenously infused rabbit autograft, allograft, and xenograft (human) BM-Muse cells in a rabbit AMI model and their mechanisms of tissue repair. <u>Methods and Results:</u> In vivo dynamics of Nano-lantern-labeled Muse cells showed preferential homing of the cells to the post-infarct heart at 3 days and 2 weeks, with ~14...
February 23, 2018: Circulation Research
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
Catalina A Lopez Gelston, Dakshnapriya Balasubbramanian, Gabriella R Abouelkheir, Alexandra H Lopez, Kayla R Hudson, Eric R Johnson, Mariappan Muthuchamy, Brett M Mitchell, Joseph M Rutkowski
<u>Rationale:</u> Hypertension is associated with renal infiltration of activated immune cells; however, the role of renal lymphatics and immune cell exfiltration is unknown. <u>Objective:</u> We tested the hypotheses that increased renal lymphatic density is associated with 2 different forms of hypertension in mice and that further augmenting renal lymphatic vessel expansion prevents hypertension by reducing renal immune cell accumulation. <u>Methods and Results:</u> Mice with salt-sensitive hypertension or nitric oxide synthase inhibition-induced hypertension exhibited significant increases in renal lymphatic vessel density and immune cell infiltration associated with inflammation...
February 23, 2018: Circulation Research
Yanbo Fan, Haocheng Lu, Wenying Liang, Minerva T Garcia-Barrio, Yanhong Guo, Ji Zhang, Tianqing Zhu, Yibai Hao, Jifeng Zhang, Y E Chen
<u>Rationale:</u> Post-ischemic angiogenesis is critical to limit the ischemic tissue damage and improve the blood flow recovery. The regulation and the underlying molecular mechanisms of post-ischemic angiogenesis are not fully unraveled. Transcription factor-EB (TFEB) is emerging as a master gene for autophagy and lysosome biogenesis. However, the role of TFEB in vascular disease is less understood. <u>Objective:</u> We aimed to determine the role of endothelial TFEB in post-ischemic angiogenesis and its underlying molecular mechanism...
February 21, 2018: Circulation Research
Petra Kleinbongard, Georgios Amanakis, Andreas Skyschally, Gerd Heusch
<u>Rationale:</u> Reduction of infarct size (IS) by remote ischemic per-conditioning (perRIC) is evident only after several hours reperfusion. <u>Objective:</u> To develop a potential real-time estimate of cardioprotection by perRIC we have analyzed the time course of ST-segment elevation. <u>Methods and Results:</u> Anesthetized open-chest pigs were subjected to 60 min coronary occlusion and 180 min reperfusion (placebo; PLA; n=19). perRIC (n=18; 4x5 min/5 min hindlimb occlusion/reperfusion) was induced 20 min after coronary occlusion...
February 21, 2018: Circulation Research
Thassio R Mesquita, Gaelle Auguste, Debora Falcón, Gema Ruiz-Hurtado, Rogelio Salazar-Enciso, Jessica Sabourin, Florence Lefebvre, Say Viengchareun, Hussein Kobeissy, Patrick Lechêne, Valerie Nicolas, Amaya Fernández-Celis, Susana Gomez, Sandra Lauton-Santos, Eric Morel, Angelica Rueda, Natalia López-Andrés, Ana M Gomez, Marc Lombes, Jean-Pierre Benitah
<u>Rationale:</u> The mineralocorticoid receptor (MR) antagonists belong to the current therapeutic armamentarium for the management of cardiovascular diseases, but the mechanisms conferring their beneficial effects are poorly understood. Part of the cardiovascular effects of MR are due to the regulation of L-type Cav 1.2 Ca2+ channel expression, which is generated by tissue-specific alternative promoters as a long 'cardiac' (Cav 1.2-LNT) or a short 'vascular' (Cav 1.2-SNT) N-terminal transcripts...
February 21, 2018: Circulation Research
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
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