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Arteriosclerosis, Thrombosis, and Vascular Biology

Kelsey E Jarrett, Ciaran Lee, Marco De Giorgi, Ayrea Hurley, Baiba K Gillard, Alexandria M Doerfler, Ang Li, Henry J Pownall, Gang Bao, William R Lagor
OBJECTIVE: Atherosclerosis studies in Ldlr knockout mice require breeding to homozygosity and congenic status on C57BL6/J background, a process that is both time and resource intensive. We aimed to develop a new method for generating atherosclerosis through somatic deletion of Ldlr in livers of adult mice. APPROACH AND RESULTS: Overexpression of PCSK9 (proprotein convertase subtilisin/kexin type 9) is currently used to study atherosclerosis, which promotes degradation of LDLR (low-density lipoprotein receptor) in the liver...
July 19, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Ileana Badi, Luigi Mancinelli, Andrea Polizzotto, Debora Ferri, Filippo Zeni, Ilaria Burba, Giuseppina Milano, Francesca Brambilla, Claudio Saccu, Marco E Bianchi, Giulio Pompilio, Maurizio C Capogrossi, Angela Raucci
OBJECTIVE: Vascular calcification (VC) is age dependent and a risk factor for cardiovascular and all-cause mortality. VC involves the senescence-induced transdifferentiation of vascular smooth muscle cells (SMCs) toward an osteochondrogenic lineage resulting in arterial wall mineralization. miR-34a increases with age in aortas and induces vascular SMC senescence through the modulation of its target SIRT1 (sirtuin 1). In this study, we aimed to investigate whether miR-34a regulates VC...
July 19, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Woo-Keun Seo, Garam Jo, Min-Jeong Shin, Kyungmi Oh
OBJECTIVE: Stroke is a heterogeneous disease with diverse causes, which affect the risk of recurrence. This study aimed to identify novel biomarkers that are clinically relevant to the diagnosis of cardioembolic stroke (CE) and the prediction of stroke recurrence using metabolomics. APPROACH AND RESULTS: We obtained blood samples and clinical data from a consecutively registered, hospital-based acute stroke registry and from healthy controls. Mass-spectrometry-based profiling was performed, and several metabolomic signatures were selected for the discrimination of CE and stroke recurrence, coupled with multivariate statistical analysis...
July 19, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Bruno Vergès, Laurence Duvillard, Jean Paul Pais de Barros, Benjamin Bouillet, Sabine Baillot-Rudoni, Alexia Rouland, Anne-Laure Sberna, Jean-Michel Petit, Pascal Degrace, Laurent Demizieux
OBJECTIVE: Treatment with liraglutide, a GLP-1 (glucagon-like peptide-1) agonist, has been shown to reduce postprandial lipidemia, an important feature of diabetic dyslipidemia. However, the underlying mechanisms for this effect remain unknown. This prompted us to study the effect of liraglutide on the metabolism of ApoB48 (apolipoprotein B48). APPROACH AND RESULTS: We performed an in vivo kinetic study with stable isotopes (D8 -valine) in the fed state in 10 patients with type 2 diabetes mellitus before treatment and 6 months after the initiation of treatment with liraglutide (1...
July 19, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Leon J DeLalio, Alexander S Keller, Jiwang Chen, Andrew K J Boyce, Mykhaylo Artamonov, Henry R Askew-Page, T C Stevenson Keller, Scott R Johnstone, Rachel B Weaver, Miranda E Good, Sara Murphy, Angela K Best, Ellen L Mintz, Silvia Penuela, Iain Greenwood, Roberto F Machado, Avril V Somlyo, Leigh Anne Swayne, Richard Minshall, Brant E Isakson
OBJECTIVE: Sympathetic nerve innervation of vascular smooth muscle cells (VSMCs) is a major regulator of arteriolar vasoconstriction, vascular resistance, and blood pressure. Importantly, α-adrenergic receptor stimulation, which uniquely couples with Panx1 (pannexin 1) channel-mediated ATP release channels in resistance arteries, also requires localization to membrane caveolae. Here, we test whether localization of Panx1 to Cav1 (caveolin-1) promotes channel function (stimulus-dependent ATP release and adrenergic vasoconstriction) and is important for blood pressure homeostasis...
July 19, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Iván Parra-Izquierdo, Irene Castaños-Mollor, Javier López, Cristina Gómez, J Alberto San Román, Mariano Sánchez Crespo, Carmen García-Rodríguez
OBJECTIVE: Calcific aortic valve disease is the most prevalent valvulopathy in Western countries. An unanticipated pathogenetic clue involving IFN (interferon) was disclosed by the finding of constitutive type I IFN activity associated with aortic valve calcification in children with the atypical Singleton-Merten syndrome. On this basis, the role of type I IFN on inflammation and calcification in human aortic valve interstitial cells (AVIC) was examined. APPROACH AND RESULTS: IFN-α was weakly proinflammatory but potentiated lipopolysaccharide-mediated activation of NF (nuclear factor)-κB and the ensuing induction of proinflammatory molecules in human AVIC...
July 19, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Hiroyuki Hirai, Bo Yang, Minerva T Garcia-Barrio, Oren Rom, Peter X Ma, Jifeng Zhang, Y Eugene Chen
OBJECTIVE: To identify the transcription factors that could contribute to direct reprogramming of fibroblasts toward smooth muscle cell fate. APPROACH AND RESULTS: We screened various combinations of transcription factors, including Myocd (myocardin), Mef2C (myocyte enhancer factor 2C), Mef2B (myocyte enhancer factor 2B), Mkl1 (MKL [megakaryoblastic leukemia]/Myocd-like 1), Gata4 (GATA-binding protein 4), Gata5 (GATA-binding protein 5), Gata6 (GATA-binding protein 6), Ets1, and their corresponding carboxyterminal fusions to the transactivation domain of MyoD-indicated by *-for their effects on reprogramming mouse embryonic fibroblasts and human adult dermal fibroblasts to the smooth muscle cell fate as determined by the expression of specific markers...
July 19, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Ayca Erbilgin, Marcus M Seldin, Xiuju Wu, Margarete Mehrabian, Zhiqiang Zhou, Hongxiu Qi, Keeyon S Dabirian, René R Sevag Packard, Wei Hsieh, Steven J Bensinger, Satyesh Sinha, Aldons J Lusis
OBJECTIVE: The objective of this study was to determine the basis of resistance to atherosclerosis of inbred mouse strain BALB/cJ. APPROACH AND RESULTS: BALB/cJ mice carry a naturally occurring null mutation of the gene encoding the transcription factor Zhx2 , and genetic analyses suggested that this may confer resistance to atherosclerosis. On a hyperlipidemic low-density lipoprotein receptor null background, BALB/cJ mice carrying the mutant allele for Zhx2 exhibited up to a 10-fold reduction in lesion size as compared with an isogenic strain carrying the wild-type allele...
July 19, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Li Wang, Yuan Wang, Chao Zhang, Jingjing Li, Yuan Meng, Man Dou, Constance Tom Noguchi, Lijun Di
OBJECTIVE: Obesity-induced inflammation in white adipose tissue, characterized by increased macrophage infiltration and associated with macrophage population shift from anti-inflammatory M2 to proinflammatory M1 macrophages, largely contributes to obesity-induced insulin resistance and influences type 2 diabetes mellitus pathogenesis. GSK3 (glycogen synthase kinase 3), a serine/threonine kinase, has been reported to participate in various cellular processes. We sought to examine the potential mechanism by which GSK3, a serine/threonine kinase implicated in various cellular processes, modulates obesity-induced visceral adipose tissue (VAT) inflammation...
July 19, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Emanuel Harari, Liang Guo, Samantha L Smith, Ka Hyun Paek, Raquel Fernandez, Atsushi Sakamoto, Hiroyoshi Mori, Matthew D Kutyna, Anwer Habib, Sho Torii, Anne Cornelissen, Hiroyuki Jinnouchi, Anuj Gupta, Frank D Kolodgie, Renu Virmani, Aloke V Finn
OBJECTIVE: Drug-eluting stents eluting canonical mTOR (mammalian target of rapamycin) inhibitors are widely used to treat coronary artery disease but accelerate the development of atherosclerosis within the stent (neoatherosclerosis)-a leading cause of late stent failure. We recently showed that canonical mTOR inhibitors bind FKBP12.6 (12.6-kDa FK506-binding protein 12), displace it from calcium release channels, resulting in activation of PKCα (protein kinase Cα) and dissociation of p-120-catenin (p120) from VE-CAD (vascular endothelial cadherin; promoting endothelial barrier dysfunction [EBD])...
July 19, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Samar R El Khoudary, Indre Ceponiene, Saad Samargandy, James H Stein, Dong Li, Matthew C Tattersall, Matthew J Budoff
OBJECTIVE: HDL-C (high-density lipoprotein cholesterol) may not always be cardioprotective in postmenopausal women. HDL particles (HDL-P) via ion-mobility may better reflect the antiatherogenicity of HDL. Objectives were (1) to evaluate associations of HDL-C and ion-mobility HDL-P with carotid intima-media thickness (cIMT) and carotid plaque separately and jointly in women; and (2) to assess interactions by age at and time since menopause. APPROACH AND RESULTS: Analysis included 1380 females from the MESA (Multi-Ethnic Study of Atherosclerosis; age: 61...
July 19, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Bela F Asztalos, Katalin V Horvath, Ernst J Schaefer
OBJECTIVE: The cell-cholesterol efflux capacity of HDL (high-density lipoprotein) is inversely associated with coronary heart disease risk. ABCA1 (ATP-binding cassette transporter A1) plays a crucial role in cholesterol efflux from macrophages to preβ-1-HDL. We tested the hypothesis that coronary heart disease patients have functionally abnormal preβ-1-HDL. APPROACH AND RESULTS: HDL cell-cholesterol efflux capacity via the ABCA1 and the SR-BI (scavenger receptor class B type I) pathways, HDL antioxidative capacity, apo (apolipoprotein) A-I-containing HDL particles, and inflammatory- and oxidative-stress markers were measured in a case-control study of 100 coronary heart disease cases and 100 sex-matched controls...
July 12, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Shuai Yuan, Arif Yurdagul, Jonette M Peretik, Mabruka Alfaidi, Zaki Al Yafeai, Sibile Pardue, Christopher G Kevil, A Wayne Orr
OBJECTIVE: Flow patterns differentially regulate endothelial cell phenotype, with laminar flow promoting vasodilation and disturbed flow promoting endothelial proinflammatory activation. CSE (cystathionine γ-lyase), a major source of hydrogen sulfide (H2 S) in endothelial cells, critically regulates cardiovascular function, by both promoting vasodilation and reducing endothelial activation. Therefore, we sought to investigate the role of CSE in the endothelial response to flow. APPROACH AND RESULTS: Wild-type C57Bl/6 and CSE knockout (CSE-/- ) mice underwent carotid partial ligation to induce disturbed flow in the left carotid...
July 12, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Jennifer B Stott, Vincenzo Barrese, Malavika Suresh, Shirou Masoodi, Iain A Greenwood
OBJECTIVE: In renal arteries, inhibitors of G protein βγ subunits (Gβγ) reduce Kv7 activity and inhibit Kv7-dependent receptor-mediated vasorelaxations. However, the mechanisms underlying receptor-mediated relaxation are artery specific. Consequently, the aim of this study was to ascertain the role of Gβγ in Kv7-dependent vasorelaxations of the rat vasculature. APPROACH AND RESULTS: Isometric tension recording was performed in isolated rat renal, mesenteric, and cerebral arteries to study isoproterenol and calcitonin gene-related peptide relaxations...
July 12, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Ricardo Villa-Bellosta
OBJECTIVE: Hydroxyapatite deposition on the medial layer of the aortic walls is the hallmark of vascular calcification and the most common complication in aging individuals and in patients with diabetes mellitus and those undergoing hemodialysis. Extracellular pyrophosphate is a potent physicochemical inhibitor of hydroxyapatite crystal formation. This study analyzed changes in extracellular pyrophosphate metabolism during the phosphate-induced calcification process. APPROACH AND RESULTS: Phosphate-induced calcification of ex vivo-cultured aortic rings resulted in calcium accumulation after 7 days...
July 12, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Carsten Behr-Rasmussen, Jes S Lindholt, Sigitas Urbonavicius, Ulrich Halekoh, Pia Søndergaard Jensen, Jane Stubbe, Lars Melholt Rasmussen, Hans Christian Beck
OBJECTIVE: Porosity of the intraluminal thrombus (ILT) is believed to convey biologically active components from the bloodstream toward the aneurismal wall. Accumulation of molecules in the abdominal aortic aneurysmatic tissue may influence vascular protein turnover and regulate abdominal aortic aneurysm growth. We sought to identify proteins with concentrations in the ILT and the abdominal aortic aneurysm wall which associate with aneurysmal expansion rate. APPROACH AND RESULTS: Proteomic analysis by liquid chromatography tandem-mass spectrometry of separated wall and ILT samples was correlated with preoperative aneurysmal growth rate in 24 individuals operated electively for infrarenal abdominal aortic aneurysm...
July 12, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Eduardo J Folco, Thomas L Mawson, Amélie Vromman, Breno Bernardes-Souza, Grégory Franck, Oscar Persson, Momotaro Nakamura, Gail Newton, Francis W Luscinskas, Peter Libby
OBJECTIVE: Coronary artery thrombosis can occur in the absence of plaque rupture because of superficial erosion. Erosion-prone atheromata associate with more neutrophil extracellular traps (NETs) than lesions with stable or rupture-prone characteristics. The effects of NETs on endothelial cell (EC) inflammatory and thrombogenic properties remain unknown. We hypothesized that NETs alter EC functions related to erosion-associated thrombosis. APPROACH AND RESULTS: Exposure of human ECs to NETs increased VCAM-1 (vascular cell adhesion molecule 1) and ICAM-1 (intercellular adhesion molecule 1) mRNA and protein expression in a time- and concentration-dependent manner...
July 5, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Ilayaraja Muthuramu, Ruhul Amin, Joseph Pierre Aboumsallem, Mudit Mishra, Emma Louise Robinson, Bart De Geest
OBJECTIVE: We investigated the hypothesis that HDL (high-density lipoprotein) dysfunction in Scarb1 -/- mice negatively affects cardiac function both in the absence and in the presence of pressure overload. Second, we evaluated whether normalization of HDL metabolism in Scarb1 -/- mice by hepatocyte-specific SR-BI (scavenger receptor class B, type I) expression after E1E3E4-deleted adenoviral AdSR-BI (E1E3E4-deleted adenoviral vector expressing SR-BI protein in hepatocytes) transfer abrogates the effects of total body SR-BI deficiency on cardiac structure and function...
July 5, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Qing Lyu, Vidhi Dhagia, Yu Han, Bing Guo, Mary E Wines-Samuelson, Christine K Christie, Qiangzong Yin, Orazio J Slivano, Paul Herring, Xiaochun Long, Sachin A Gupte, Joseph M Miano
OBJECTIVE: Unreliable antibodies often hinder the accurate detection of an endogenous protein, and this is particularly true for the cardiac and smooth muscle cofactor, MYOCD (myocardin). Accordingly, the mouse Myocd locus was targeted with 2 independent epitope tags for the unambiguous expression, localization, and activity of MYOCD protein. APPROACH AND RESULTS: 3cCRISPR (3-component clustered regularly interspaced short palindromic repeat) was used to engineer a carboxyl-terminal 3×FLAG or 3×HA epitope tag in mouse embryos...
July 5, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Arash Haghikia, Xinmin S Li, Thomas G Liman, Nils Bledau, David Schmidt, Friederike Zimmermann, Nicolle Kränkel, Christian Widera, Kristina Sonnenschein, Aiden Haghikia, Karin Weissenborn, Daniela Fraccarollo, Markus M Heimesaat, Johann Bauersachs, Zeneng Wang, Weifei Zhu, Udo Bavendiek, Stanley L Hazen, Matthias Endres, Ulf Landmesser
OBJECTIVE: Gut microbiota-dependent metabolites, in particular trimethylamine N -oxide (TMAO), have recently been reported to promote atherosclerosis and thrombosis. Here, we examined for the first time the relation of TMAO and the risk of incident cardiovascular events in patients with recent first-ever ischemic stroke in 2 independent prospective cohorts. Moreover, the link between TMAO and proinflammatory monocytes as a potential contributing factor for cardiovascular risk in stroke patients was studied...
July 5, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
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