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Circulation Research

Kyuho Jeong, Jung-Hyun Kim, James M Murphy, Hyeonsoo Park, Su-Jeong Kim, Yelitza Rodriguez, Hyunkyung Kong, Chungsik Choi, Jun-Lin Guan, Joan M Taylor, Thomas M Lincoln, William T Gerthoffer, Jun-Sub Kim, Eun-Young Erin Ahn, David D Schlaepfer, Ssang-Taek Steve Lim
RATIONALE: Neointimal hyperplasia is characterized by excessive accumulation of vascular smooth muscle cells (SMCs) leading to occlusive disorders such as atherosclerosis and stenosis. Blood vessel injury increases growth factor secretion and matrix synthesis, which promotes SMC proliferation and neointimal hyperplasia via focal adhesion kinase (FAK). OBJECTIVE: To understand the mechanism of FAK action in SMC proliferation and neointimal hyperplasia. METHODS AND RESULTS: Using combined pharmacological FAK catalytic inhibition (VS-4718) and SMC-specific FAK kinase-dead (KD, Myh11-Cre-ERT2) mouse models, we report that FAK regulates SMC proliferation and neointimal hyperplasia in part by governing GATA4-cyclin D1 signaling...
May 17, 2019: Circulation Research
Bijun Chen, Shuaibo Huang, Ya Su, Yi-Jin Wu, Anis Hanna, Adipong Brickshawana, Jonathan M Graff, Nikolaos G Frangogiannis
RATIONALE: Transforming Growth Factor (TGF)-β is critically involved in myocardial injury, repair and fibrosis, activating both Smad-dependent and non-Smad pathways. The in vivo role of TGFβ signaling in regulation of macrophage function is poorly understood. We hypothesized that in the infarcted myocardium, activation of TGF-β/Smad signaling in macrophages may regulate repair and remodeling. OBJECTIVE: To investigate the role of macrophage-specific TGFβ/Smad3 signaling in a mouse model of myocardial infarction (MI) and to dissect the mechanisms mediating Smad-dependent modulation of macrophage function...
May 16, 2019: Circulation Research
Chi Keung Lam, Lei Tian, Nadjet Belbachir, Rajani Shrestha, Ning Ma, Tomoya Kitani, June-Wha Rhee, Alexa Wnorowski, Joseph C Wu
RATIONALE: Calcium channel blockers (CCBs) are an important class of drugs in managing cardiovascular diseases. Patients usually rely on these medications for the remainder of their lives after diagnosis. Although the acute pharmacological actions of CCBs in the hearts are well-defined, little is known about the drug-specific effects on human cardiomyocyte transcriptomes and physiological alterations after long-term exposure. OBJECTIVE: This study aimed to simulate chronic CCB treatment and to examine both the functional and transcriptomic changes in human cardiomyocytes...
May 13, 2019: Circulation Research
Zhichao Ni, Jiacheng Deng, Claire Mf Potter, Witold Norbert Nowak, Wenduo Gu, Zhongyi Zhang, Ting Chen, Qishan Chen, Yanhua Hu, Bin Zhou, Qingbo Xu, Li Zhang
RATIONALE: Transplantation-accelerated arteriosclerosis is one of the major challenges for long-term survival of patients with solid organ transplantation. Although stem/progenitor cells (SPCs) have been implicated to participate in this process, the cells of origin and underlying mechanisms have not been fully defined. OBJECTIVE: The objective of our study was to investigate the role of c-Kit lineage cells in allograft-induced neointima formation, and to explore the mechanisms underlying this process...
May 13, 2019: Circulation Research
Laurent Calvier, Philippe Boucher, Joachim Herz, Georg Hansmann
RATIONALE: Arterial remodeling, a hallmark of many cardiovascular pathologies including pulmonary arterial hypertension (PAH), is regulated by TGFβ1-TGFβ receptors and the antagonistic, vasoprotective BMPR2-PPARγ axis. However, it is unclear which factors drive detrimental TGFβ1 pathways in the hypertensive pulmonary vasculature. OBJECTIVE: We hypothesized that LDL receptor-related protein1 (LRP1) expression is decreased in PAH, leading to enhancement (disinhibition) of TGFβ1 signals, and that the PPARγ agonist pioglitazone can restore vascular homeostasis and prevent PAH resulting from LRP1 deletion in vascular smooth muscle cells (VSMC)...
April 26, 2019: Circulation Research
Ying Zhang, Wei Eric Wang, Xiaoying Zhang, Ying Li, Biyi Chen, Chong Liu, Xiaojie Ai, Xiaoxiao Zhang, Ying Tian, Chen Zhang, Mingxin Tang, Christopher Szeto, Xiang Hua, Mingxing Xie, Chunyu Zeng, Yingjie Wu, Lin Zhou, Weizhong Zhu, Daohai Yu, Steven R Houser, Xiongwen Chen
RATIONALE: Protein Kinase A (PKA) is a major mediator of β-adrenergic (βAR) regulation of cardiac function but other mediators have also been suggested. Reduced PKA basal activity and activation are linked to cardiac diseases. However, how complete loss of PKA activity impacts on cardiac physiology and if it causes cardiac dysfunction have never been determined. OBJECTIVE: We set to determine how the heart adapts to the loss of cardiomyocyte PKA activity and if it elicits cardiac abnormalities...
April 15, 2019: Circulation Research
Alexander Kurilshikov, Inge Cl van den Munckhof, Lianmin Chen, Marc Jan Bonder, Kiki Schraa, Joost Rutten, Niels P Riksen, Jacqueline de Graaf, Marije Oosting, Serena Sanna, Leo Ab Joosten, Marinette van der Graaf, Tessa Brand, Debby Py Koonen, Martijn Jr van Faassen, P Eline Slagboom, Ramnik J Xavier, Folkert Kuipers, Marten Hofker, Cisca Wijmenga, Mihai G Netea, Alexandra Zhernakova, Jingyuan Fu
RATIONALE: Altered gut microbial composition has been linked to cardiovascular diseases (CVD), but its functional links to host metabolism and immunity in relation to CVD development remain unclear. OBJECTIVE: To systematically assess functional links between the microbiome and the plasma metabolome, cardiometabolic phenotypes and CVD risk and to identify diet-microbe-metabolism-immune interactions in well-documented cohorts. METHODS AND RESULTS: We assessed metagenomics-based microbial associations between 231 plasma metabolites and microbial species and pathways in the population-based Lifelines-DEEP cohort (n=978) and a clinical obesity cohort (n=297)...
April 11, 2019: Circulation Research
Austin Borden, Justin Kurian, Emily Nickoloff, Yijun Yang, Constantine Troupes, Jessica Ibetti, Anna Maria Lucchese, Erhe Gao, Sadia Mohsin, Walter J Koch, Steven R Houser, Raj Kishore, Mohsin Khan
RATIONALE: Embryonic heart is characterized by of rapidly dividing cardiomyocytes required to build a working myocardium. Cardiomyocytes retain some proliferative capacity in the neonates but lose it in adulthood. Consequently, a number of signaling hubs including microRNAs are altered during cardiac development that adversely impacts regenerative potential of cardiac tissue. Embryonic stem cell cycle (ESCC) miRs are a class of microRNAs exclusively expressed during developmental stages however their effect on cardiomyocyte proliferation and heart function in adult myocardium has not been previously studied...
April 9, 2019: Circulation Research
Alexander Joerk, Marcel Ritter, Niklas Langguth, Raphael Andreas Seidel, Diana Freitag, Karl-Heinz Herrmann, Anna Schaefgen, Marvin Ritter, Milena Guenther, Charline Sommer, Dirk Braemer, Jan Walter, Christian Ewald, Rolf Kalff, Juergen R Reichenbach, Matthias Westerhausen, Georg Pohnert, Otto W Witte, Knut Holthoff
RATIONALE: Delayed ischemic neurological deficit is the most common cause of neurological impairment and unfavorable prognosis in subarachnoid hemorrhage (SAH) patients. Despite the existence of neuroimaging modalities that depict the onset of the accompanying cerebral vasospasm, preventive and therapeutic options are limited and fail to improve outcome owing to an insufficient pathomechanistic understanding of the delayed perfusion deficit. Previous studies have suggested that bilirubin oxidation products (BOXes), originating from released heme surrounding ruptured blood vessels, are involved in arterial vasoconstriction...
April 5, 2019: Circulation Research
Roman Günthner, Henner Hanssen, Christine Hauser, Susanne Angermann, Georg Lorenz, Stephan Kemmner, Julia Matschkal, Matthias C Braunisch, Claudius Kuechle, Lutz Renders, Philipp Moog, Siegfried Wassertheurer, Marcus Baumann, Hans-Peter Hammes, Christopher C Mayer, Bernhard Haller, Sarah Stryeck, Tobias Madl, Javier Carbajo-Lozoya, Uwe Heemann, Konstantin Kotliar, Christoph Schmaderer
RATIONALE: Patients with end-stage renal disease (ESRD) are characterized by increased cardiovascular (CV) and all-cause mortality due to advanced remodeling of the macro- and microvascular beds. OBJECTIVE: The aim of this study was to determine whether retinal microvascular function can predict all-cause and CV mortality in patients with ESRD. METHODS AND RESULTS: In the multicenter prospective observational ISAR (Risk Stratification in End-Stage Renal Disease) study, data on dynamic retinal vessel analysis (DVA) was available in a sub-cohort of 214 dialysis patients (mean age 62...
April 1, 2019: Circulation Research
Thomas Stiermaier, Jan-Oluf Jensen, Karl-Philipp Rommel, Suzanne de Waha-Thiele, Georg Fuernau, Steffen Desch, Holger Thiele, Ingo Eitel
RATIONALE: Remote ischemic conditioning (RIC) and/or ischemic postconditioning (PostC) may protect the myocardium from ischemia-reperfusion injury in patients with ST-elevation myocardial infarction (STEMI). OBJECTIVE: To determine whether combined intrahospital RIC and PostC or PostC alone in addition to primary percutaneous coronary intervention (PCI) reduce long-term clinical events after STEMI. METHODS AND RESULTS: The present study is a post-hoc analysis of a prospective trial which randomized 696 STEMI patients with symptoms <12 hours 1:1:1 to either combined RIC and PostC in addition to primary PCI, PostC alone in addition to primary PCI, or conventional PCI (control)...
April 1, 2019: Circulation Research
Kimberly J Dunham-Snary, Danchen Wu, Francois Potus, Edward A Sykes, Jeffrey D Mewburn, Rebecca L Charles, Philip Eaton, Richard A Sultanian, Stephen L Archer
RATIONALE: Hypoxic pulmonary vasoconstriction (HPV) optimizes systemic oxygen delivery by matching ventilation to perfusion. HPV is intrinsic to pulmonary artery smooth muscle cells (PASMC). Hypoxia dilates systemic arteries, including renal arteries. Hypoxia is sensed by changes in mitochondrial-derived reactive oxygen species, notably H2 O2 ([H2 O2 ]mito ). Decreases in [H2 O2 ]mito elevate pulmonary vascular tone by increasing intracellular calcium ([Ca2+ ]i ) through redox regulation of ion channels...
March 29, 2019: Circulation Research
Daniel A Jones, Deshan Weeraman, Martina Colicchia, Mohsin A Hussain, Devanayegi Veerapen, Mervyn Andiapen, Krishnaraj S Rathod, Andreas Baumbach, Anthony Mathur
RATIONALE: Cell based therapies are a novel potential treatment for refractory angina (RFA) and have been found to improve markers of angina. However, the effects on mortality and major adverse cardiac events (MACE) have not been definitively investigated. OBJECTIVE: To investigate the efficacy and safety of stem cell treatment compared with optimal medical treatment (OMT) for RFA by conducting an updated meta-analysis, looking at clinical outcomes. METHODS AND RESULTS: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) using the PRISMA guidelines...
March 29, 2019: Circulation Research
Anne Petz, Maria Grandoch, Daniel J Gorski, Marcel Abrams, Marco André Piroth, Rebekka Schneckmann, Susanne Homann, Julia Müller, Sonja Hartwig, Stefan Lehr, Yu Yamaguchi, Thomas N Wight, Simone Gorressen, Zhaoping Ding, Sebastian Kötter, Martina Krüger, Andre Heinen, Malte Kelm, Axel Gödecke, Ulrich Flögel, Jens W Fischer
RATIONALE: Immediate changes in the extracellular matrix (ECM) microenvironment occur after myocardial ischemia and reperfusion injury (I/R). OBJECTIVE: Aim of this study was to unravel the role of the early hyaluronan (HA)-rich ECM after I/R. METHODS AND RESULTS: Genetic deletion of HA synthase 2 (Has2) and Has1 were used in a murine model of cardiac I/R. Chemical exchange saturation transfer (CEST) imaging was adapted to image cardiac ECM post I/R...
March 27, 2019: Circulation Research
Xiaohong H Shu, Claire A Ruddiman, Tc Stevenson Keller, Alexander S Keller, Yang Yang, Miranda E Good, Angela K Best, Linda Columbus, Brant E Isakson
RATIONALE: Resistance arteries and conduit arteries rely upon different relative contributions of endothelial derived hyperpolarization (EDH) versus nitric oxide (NO) to achieve dilatory heterocellular signaling. Anatomically, resistance arteries use myoendothelial junctions (MEJs), endothelial cell (EC) projections that make contact with smooth muscle cells (SMCs). Conduit arteries have very few to no MEJs. OBJECTIVE: Determine if the presence of MEJs in conduit arteries can alter heterocellular signaling...
March 22, 2019: Circulation Research
Jian Guo, Ziying Wang, Jichao Wu, Min Liu, Mengmeng Li, Yu Sun, Wei Huang, Yujia Li, Yan Zhang, Wei Tang, Xiaoyan Li, Chun Zhang, Fanzhen Hong, Ningjun Li, Jing Nie, Fan Yi
RATIONALE: Endothelial dysfunction is an important determinant risk factor for the development of hypertension and its complications. Thus, identification of potential therapeutic targets for preventing endothelial dysfunction has major clinical importance. Emerging evidence indicates that epigenetic modifications are closely associated with the regulation of endothelial function. Among them, histone deacetylase (HDAC)-mediated epigenetic processes in vascular homeostasis and cardiovascular disease have attracted much attention...
March 21, 2019: Circulation Research
Viktoria Kalna, Youwen Yang, Claire Peghaire, Karen Frudd, Rebecca Hannah, Aarti V Shah, Lourdes Osuna Almagro, Joseph J Boyle, Berthold Göttgens, Jorge Ferrer, Anna M Randi, Graeme M Birdsey
RATIONALE: The ETS transcription factor (TF) ERG is essential for endothelial homeostasis, driving expression of lineage genes and repressing pro-inflammatory genes. Loss of ERG expression is associated with diseases including atherosclerosis. ERG's homeostatic function is lineage-specific, since aberrant ERG expression in cancer is oncogenic. The molecular basis for ERG lineage-specific activity is unknown. Transcriptional regulation of lineage specificity is linked to enhancer clusters (super-enhancers)...
March 20, 2019: Circulation Research
Yoosoo Chang, Jae Heon Kim, Jin-Won Noh, Young Sam Cho, Heung Jae Park, Kwan Joong Joo, Seungho Ryu
RATIONALE: Although prostate-specific antigen (PSA), a tumor marker for prostate cancer, has been reported to be associated with cardiovascular disease (CVD) risk factors, studies on the association of PSA with subclinical and clinical CVD remain limited. OBJECTIVE: We examined the association of total serum PSA within the reference range with coronary artery calcium (CAC) score and CVD mortality. METHODS AND RESULTS: A cross-sectional study was performed in 88,203 Korean men who underwent a health checkup exam including cardiac tomography estimation of CAC score...
March 19, 2019: Circulation Research
Ye Fan, Yikuan Chen, Jing Zhang, Feng Yang, Yanhua Hu, Li Zhang, Chunyu Zeng, Qingbo Xu
RATIONALE: RNA helicases, highly conserved enzymes, are currently believed to be not only involved in RNA modulation, but also in other biological processes. We recently reported that RNA helicase DEAD-box protein 5 (DDX5) is required for maintaining the homeostasis of vascular smooth muscle cells (SMCs). However, the expression and function of RNA helicase in vascular physiology and disease is unknown. OBJECTIVE: To investigate the role of RNA helicase in vascular diseases...
March 18, 2019: Circulation Research
Zuoxu Hou, Xinghua Qin, Yuanyuan Hu, Xing Zhang, Guohua Li, Jie Wu, Jia Li, Jianding Sha, Jiangwei Chen, Jielai Xia, Lifeng Wang, Feng Gao
RATIONALE: Exercise training, in addition to reducing cardiovascular risk factors, confers direct protection against myocardial ischemia/reperfusion (MI/R) injury and has been associated with improved heart-attack survival in humans. However, the underlying mechanisms of exercise-afforded cardioprotection are still unclear. OBJECTIVE: To investigate the role of exercise-derived circulating exosomes in cardioprotection and the molecular mechanisms involved. METHODS AND RESULTS: Circulating exosomes were isolated from the plasma of volunteers with or without exercise training and rats subjected to 4-week swim exercise or sedentary littermates 24 hours after the last training session...
March 18, 2019: Circulation Research
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