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| Open AccessRegulation of angiotensin II actions by enhancers and super-enhancers in vascular smooth muscle cells
The repertoire of tissue-specific distal regulators of gene transcription enhancers defines homeostasis or disease. Here, the authors reveal the enhancer and super-enhancer signature of vascular smooth muscle cells under normal and angiotensin II stimuli, providing new insight into the transcriptional regulation of vascular pathologies.
- Sadhan Das
- , Parijat Senapati
- & Rama Natarajan
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Article
| Open AccessMammalian γ2 AMPK regulates intrinsic heart rate
AMPK regulates cellular energy balance using its γ subunit as an energy sensor of cellular AMP and ADP to ATP ratios. Here, the authors show that γ2 AMPK activation lowers heart rate by reducing the activity of pacemaker cells, whereas loss of γ2 AMPK increases heart rate and prevents the adaptive bradycardia of endurance training in mice.
- Arash Yavari
- , Mohamed Bellahcene
- & Houman Ashrafian
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Article
| Open AccessReducing sarcolipin expression mitigates Duchenne muscular dystrophy and associated cardiomyopathy in mice
Sarcolipin is an inhibitor of the ATP dependent calcium pump SERCA, and is abnormally elevated in Duchenne muscular dystrophy. The authors show that reducing sarcolipin expression ameliorates skeletal muscle pathology and cardiomyopathy and extends life span in mouse models of DMD.
- Antanina Voit
- , Vishwendra Patel
- & Gopal J. Babu
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Article
| Open AccessBlood vessel control of macrophage maturation promotes arteriogenesis in ischemia
Molecular mechanisms of macrophage-mediated regulation of artery growth in response to ischemia are poorly understood. Here the authors show that vascular endothelium controls macrophage maturation and differentiation via Notch signaling, which in turn promotes arteriogenesis and ischemic tissue recovery.
- Kashyap Krishnasamy
- , Anne Limbourg
- & Florian P. Limbourg
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Article
| Open AccessA conserved KLF-autophagy pathway modulates nematode lifespan and mammalian age-associated vascular dysfunction
KLF family transcription factors (KLFs) regulate many cellular processes, including proliferation, survival and stress responses. Here, the authors position KLFs as important regulators of autophagy and lifespan in C. elegans, a role that may extend to the modulation of age-associated vascular phenotypes in mammals.
- Paishiun N. Hsieh
- , Guangjin Zhou
- & Mukesh K. Jain
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Article
| Open AccessLoss of β-catenin in resident cardiac fibroblasts attenuates fibrosis induced by pressure overload in mice
Understanding the mechanisms causing cardiac fibrosis is key to prevention and therapy development of many heart diseases. Here, the authors show that Wnt/β-catenin signaling in resident cardiac fibroblasts is required for deposition of fibrotic extracellular matrix and the regulation of cardiomyocyte hypertrophy in a mouse model of heart fibrosis.
- Fu-Li Xiang
- , Ming Fang
- & Katherine E. Yutzey
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Article
| Open AccessHeparan sulfate proteoglycans present PCSK9 to the LDL receptor
PCSK9 interacts with LDL receptor, causing its degradation, and consequently reduces the clearance of LDL. Here, Gustafsen et al. show that PCSK9 interacts with heparan sulfate proteoglycans and this binding favors LDLR degradation. Pharmacological inhibition of this binding can be exploited as therapeutic intervention to lower LDL levels.
- Camilla Gustafsen
- , Ditte Olsen
- & Simon Glerup
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Article
| Open AccessMetabolic stress-induced cardiomyopathy is caused by mitochondrial dysfunction due to attenuated Erk5 signaling
The mechanistic link between metabolic stress and associated cardiomyopathy is unknown. Here the authors show that high fat diet causes calpain-1-dependent degradation of ERK5 leading to mitochondrial dysfunction, suggesting the maintenance of cardiac ERK5 as a therapeutic approach for cardiomyopathy prevention and/or treatment.
- Wei Liu
- , Andrea Ruiz-Velasco
- & Xin Wang
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Article
| Open AccessThrombopoiesis is spatially regulated by the bone marrow vasculature
Megakaryocyte maturation is thought to occur as the cells migrate from a vessel-distant (endosteal) niche to the vessel within the bone. Here, the authors show that megakaryocytes represent largely sessile cells in close contact with the vasculature and homogeneously distributed in the bone marrow.
- David Stegner
- , Judith M. M. vanEeuwijk
- & Katrin G. Heinze
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Article
| Open AccessPlakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm
It is believed that mutations in desmosomal adhesion complex protein plakophilin 2 (PKP2) cause arrhythmia due to loss of cell-cell communication. Here the authors show that PKP2 controls the expression of proteins involved in calcium cycling in adult mouse hearts, and that lack of PKP2 can cause arrhythmia in a structurally normal heart.
- Marina Cerrone
- , Jerome Montnach
- & Mario Delmar
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Article
| Open AccessIdentification of a hybrid myocardial zone in the mammalian heart after birth
Fetal trabecular muscles in the heart undergo a poorly described morphogenetic process that results into a solidified compact myocardium after birth. Tian et al. show that cardiomyocytes in the fetal compact layer also contribute to this process, forming a hybrid myocardial zone that is composed of cells derived from both trabecular and compact layers.
- Xueying Tian
- , Yan Li
- & Bin Zhou
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Article
| Open AccessNear-infrared autofluorescence induced by intraplaque hemorrhage and heme degradation as marker for high-risk atherosclerotic plaques
Atherosclerosis diagnosis relies primarily on imaging and early detection of high-risk atherosclerotic plaques is important for risk stratification of patients and stabilization therapies. Here Htun et al. demonstrate that vulnerable atherosclerotic plaques generate near-infrared autofluorescence that can be detected via emission computed tomography.
- Nay Min Htun
- , Yung Chih Chen
- & Karlheinz Peter
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Article
| Open AccessMiR-497∼195 cluster regulates angiogenesis during coupling with osteogenesis by maintaining endothelial Notch and HIF-1α activity
H-type endothelium, defined by the high expression of CD31 and endomucin, is found in the bone where it promotes angiogenesis and osteogensis. Here Yanget al. show that the miR-497∼195 cluster regulates the generation and maintenance of the H-type endothelium by controlling the levels of Notch regulator Fbxw7 and the HIF regulator P4HTM.
- Mi Yang
- , Chang-Jun Li
- & Xiang-Hang Luo
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Article
| Open AccessGenetic loci associated with heart rate variability and their effects on cardiac disease risk
Heart rate variability (HRV) describes the individual variation in cardiac cycle duration and is a measure of vagal control of heart rate. Here, the authors identify seventeen single-nucleotide polymorphisms associated with HRV, lending new insight into the vagal regulation of heart rhythm.
- Ilja M. Nolte
- , M. Loretto Munoz
- & Eco J. C. de Geus
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Article
| Open AccessType-2 innate lymphoid cells control the development of atherosclerosis in mice
Type-2 innate lymphoid cells (ILC2) affect adipose tissue metabolism and function. Here the authors show that the ILC2 are present in para-aortic adipose tissue and represent a major source of IL-5 and IL-13 required for mounting atheroprotective immunity, which can be altered by high fat diet.
- Stephen A. Newland
- , Sarajo Mohanta
- & Ziad Mallat
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Article
| Open AccessExploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis
Dysfunction of autophagy in plaque macrophages aggravates atherosclerosis. Here the authors show that induction of macrophage autophagy–lysosomal biogenesis either genetically by overexpression of the master transcriptional regulator of this process, TFEB, or pharmacologically with trehalose is atheroprotective.
- Ismail Sergin
- , Trent D. Evans
- & Babak Razani
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Article
| Open AccessThe critical role of SENP1-mediated GATA2 deSUMOylation in promoting endothelial activation in graft arteriosclerosis
A major cause of transplanted organ failure is graft arteriosclerosis. Qiuet al. show that a key protease of post-translational SUMO modification, SENP1, is crucial for graft arteriosclerosis by regulating the activity of GATA2 transcription factor in the endothelium, and promoting endothelial inflammation and alloimmunity.
- Cong Qiu
- , Yuewen Wang
- & Luyang Yu
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Article
| Open AccessCellular interplay via cytokine hierarchy causes pathological cardiac hypertrophy in RAF1-mutant Noonan syndrome
The human congenital disorder Noonan Syndrome (NS) is caused by germ-line mutations that hyperactivate the RAS/ERK signalling pathway, and can feature pathologic cardiac enlargement. Here, the authors find that a complex cellular and molecular interplay involving a cytokine hierarchy underlies cardiac hypertrophy caused by a NS-associatedRafallele.
- Jiani C. Yin
- , Mathew J. Platt
- & Benjamin G. Neel
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Article
| Open AccessProtein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve
Bicuspid aortic valve (BAV) is the most common human congenital cardiovascular malformation. Here, the authors perform a genome-wide association study for BAV and identify risk variants in the gene region of cardiac-specific transcription factor GATA4 and implicate GATA4 in heart valve development.
- Bo Yang
- , Wei Zhou
- & Cristen J. Willer
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Article
| Open AccessDNA single-strand break-induced DNA damage response causes heart failure
DNA damage response (DDR) is activated in cardiomyocytes of the failing heart, but the type of DNA damage leading to DDR is unclear. Higoet al. show that in mice heart failure is caused in part by unrepaired DNA single-strand breaks in cardiomyocytes, which activate persistent DDR and trigger an NF-κB-dependent cardiac inflammation.
- Tomoaki Higo
- , Atsuhiko T. Naito
- & Issei Komuro
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Article
| Open AccessNeutrophil stunning by metoprolol reduces infarct size
Metoprolol is a selective β1 adrenergic receptor blocker that reduces cardiac infarct size and improves cardiac function. The drug is believed to act on cardiomyocytes; however, here the authors show that metoprolol exerts its beneficial effect on infarcted heart by targeting neutrophils and altering their function and interaction with platelets.
- Jaime García-Prieto
- , Rocío Villena-Gutiérrez
- & Borja Ibanez
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Article
| Open AccessThe histone H3K9 methyltransferase SUV39H links SIRT1 repression to myocardial infarction
The molecular pathways regulating the cardioprotective activity of deacetylase sirtuin-1 are unknown. Here, Yanget al. show that histone H3K9 methyltransferase SUV39H and HP1gamma cooperatively methylate H3K9 on the sirtuin-1 promoter and inhibit sirtuin-1 transcription, and show that inhibition of SUV39H in mice is cardioprotective.
- Guang Yang
- , Xinyu Weng
- & Aijun Sun
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Article
| Open AccessT cell costimulation blockade blunts pressure overload-induced heart failure
Abatacept is an FDA-approved drug used for treatment of rheumatoid arthritis. Here the authors show that abatacept reduces cardiomyocyte death in a mouse model of heart failure by inhibiting activation and heart infiltration of T cells and macrophages, an effect mediated by IL-10, suggesting a potential therapy for heart failure.
- Marinos Kallikourdis
- , Elisa Martini
- & Gianluigi Condorelli
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Article
| Open AccessActivation of E-prostanoid 3 receptor in macrophages facilitates cardiac healing after myocardial infarction
Acute myocardial infarction (AMI) triggers sterile inflammatory reaction mediated by prostaglandin E2 (PGE2). Tang et al. show that the PGE2 via its receptor EP3 promotes cardiac healing after AMI by recruiting reparative Ly6Clowmonocytes/macrophages, which is mediated by TGF-β-driven regulation of CX3CR1 expression and VEGF secretion.
- Juan Tang
- , Yujun Shen
- & Ying Yu
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Review Article
| Open AccessThe molecular basis of endothelial cell plasticity
Vascular endothelium possesses remarkable plasticity in response to cues from its surroundings, leading to great heterogeneity of endothelial cells in different vascular beds. Here the authors explain the molecular basis of endothelial plasticity during embryogenesis and in various diseases.
- Elisabetta Dejana
- , Karen K. Hirschi
- & Michael Simons
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Article
| Open AccessDisruption of cardiac cholinergic neurons enhances susceptibility to ventricular arrhythmias
Catheter ablation is a common therapy for atrial fibrillation but disrupts cardiac cholinergic neurons. Here the authors report that cholinergic neurons innervate heart ventricles and show that their ablation leads to increased susceptibility to ventricular arrhythmias in mouse models and in patients.
- Christiane Jungen
- , Katharina Scherschel
- & Christian Meyer
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Article
| Open AccessPolyglucose nanoparticles with renal elimination and macrophage avidity facilitate PET imaging in ischaemic heart disease
In vivo imaging of inflammation is crucial for detection and monitoring of many pathologies and noninvasive macrophage quantification has been suggested as a possible approach. Here Keliher et al. describe novel polyglucose nanoparticle tracers that are rapidly excreted by the kidney and with high affinity for macrophages in atherosclerotic plaques.
- Edmund J. Keliher
- , Yu-Xiang Ye
- & Matthias Nahrendorf
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Article
| Open AccessTherapeutic microparticles functionalized with biomimetic cardiac stem cell membranes and secretome
Stem cells exert their beneficial effects through secretion of regenerative factors. Here, the authors take the membranes and secreted factors from cardiac stem cells and generate a synthetic cell-mimicking microparticle, which, on injection in a mouse model of myocardial infarction, improves cardiac function.
- Junnan Tang
- , Deliang Shen
- & Ke Cheng
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Article
| Open AccessSaturated palmitic acid induces myocardial inflammatory injuries through direct binding to TLR4 accessory protein MD2
The free fatty acid-mediated inflammatory activities are regulated through TLR4. Here the authors show that palmitic acid binds to MD2, initiating complex formation with TLR4, recruitment of MyD88, and subsequent activation of pro-inflammatory molecules, and that MD2 blockade protects against diet-induced cardiac dysfunction.
- Yi Wang
- , Yuanyuan Qian
- & Guang Liang
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Article
| Open AccessTargeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment
Lysyl oxidase-like 2 (LOXL2) is an enzyme that promotes scaffolding of extracellular matrix proteins. Here the authors show that LOXL2 is crucial for pressure-overload induced cardiac fibrosis, and that antibody-mediated inhibition or genetic disruption ofLoxl2in mice shows therapeutic potential for treatment of cardiac fibrosis.
- Jin Yang
- , Konstantinos Savvatis
- & Ching-Pin Chang
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Article
| Open AccessPI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia
Arteriovenous malformations (AVM) is a hallmark of hereditary haemorrhagic telangiectasia type 2, a disease caused by mutations in BMP receptor ALK1. Ola et al. show that AVM can be caused by blocking BMP9 and BMP10 in mice, leading to increased VEGF and PI3K activity, and that pharmacologic inhibition of PI3K prevents AVM development.
- Roxana Ola
- , Alexandre Dubrac
- & Anne Eichmann
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Article
| Open AccessGenome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells
Atherosclerosis is caused by low-density lipoprotein (LDL) buildup in the vessel wall, a process thought to be mediated by LDL receptor alone. Here, the authors show that the endothelium can uptake LDL via ALK1, a TGFβ signalling receptor, suggesting new therapies for blocking LDL accumulation in the vessel wall.
- Jan R. Kraehling
- , John H. Chidlow
- & William C. Sessa
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Article
| Open AccessThe persistence of low-grade inflammatory monocytes contributes to aggravated atherosclerosis
Chronic low-grade inflammation has been suspected to promote atherosclerosis. Here, Geng et al. show that sustained low-grade inflammation promotes atherosclerosis in mice via monocyte programing that involves a coupled disruption of IRAK-M regulation and induction of miR-24.
- Shuo Geng
- , Keqiang Chen
- & Liwu Li
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Article
| Open AccessPARP9 and PARP14 cross-regulate macrophage activation via STAT1 ADP-ribosylation
Signalling pathways that mediate macrophage activation in disease are poorly understood. Here the authors show that inhibition of PARP9 and/or activation of PARP14 may attenuate macrophage-mediated vascular diseases, and also provide new insight into the development of effective therapies for other inflammatory disorders.
- Hiroshi Iwata
- , Claudia Goettsch
- & Masanori Aikawa
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Article
| Open AccessDisulfide-activated protein kinase G Iα regulates cardiac diastolic relaxation and fine-tunes the Frank–Starling response
The stroke volume of the heart increases in response to an increase in the blood volume filling the heart. Here the authors reveal that this coordinated process is mediated in part by oxidative activation of the protein kinase G Iα, which phosphorylates phospholamban to enhance diastolic relaxation in mice.
- Jenna Scotcher
- , Oleksandra Prysyazhna
- & Philip Eaton
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Article
| Open AccessTREM-1 links dyslipidemia to inflammation and lipid deposition in atherosclerosis
TREM-1 is a receptor that amplifies acute pro-inflammatory responses in infection. Here the authors show that TREM-1 plays an important role in atherosclerosis, a chronic and non-infectious disease, by critically skewing myelopoiesis towards preferential monocyte differentiation and by contributing to CD36-driven cellular lipid accumulation.
- Daniel Zysset
- , Benjamin Weber
- & Christoph Mueller
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Article
| Open AccessCaMKII induces permeability transition through Drp1 phosphorylation during chronic β-AR stimulation
β-adrenergic receptor signaling induces mitochondrial permeability transition pore (mPTP) opening. Here, Xuet al. show that this effect is mediated by phosphorylation of mitochondrial fission protein Drp1 by CamKII, which increases the frequency of transient mPTP opening.
- Shangcheng Xu
- , Pei Wang
- & Wang Wang
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Article
| Open AccessGlobal and hepatocyte-specific ablation of Bmal1 induces hyperlipidaemia and enhances atherosclerosis
Bmal1 is a key transcription factor that controls rhythmicity of diverse biological functions. Here, Pan et al. show that Bmal1 deficiency in mice increases lipoprotein secretion and reduces cholesterol excretion to bile, and decipher the molecular mechanisms underlying hyperlipidaemia and atherosclerosis promoted by the lack of Bmal1.
- Xiaoyue Pan
- , Christopher A. Bradfield
- & M. Mahmood Hussain
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Article
| Open AccessFhf2 gene deletion causes temperature-sensitive cardiac conduction failure
Fever is a defence mechanism against infection, but it may also cause abnormal heart rhythm viaunknown mechanism. Here the authors identify FHF2 protein as a key regulator of myocardial excitability that protects the heart against conduction failure in response to an increase in body temperature.
- David S. Park
- , Akshay Shekhar
- & Glenn I. Fishman
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Article
| Open AccessANGPTL2 activity in cardiac pathologies accelerates heart failure by perturbing cardiac function and energy metabolism
Heart responds to increased workload by enlarging cardiomyocytes to preserve function, but in pathologies hypertrophy leads to heart failure. Here the authors show that ANGPTL2 activity in the heart is critical for determining beneficial vs. pathological hypertrophy via its effect on AKT-SERCA2a signaling and myocardial energy.
- Zhe Tian
- , Keishi Miyata
- & Yuichi Oike
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Article
| Open Access14-3-3ζ regulates the mitochondrial respiratory reserve linked to platelet phosphatidylserine exposure and procoagulant function
Platelets express negatively charged phosphatidylserine (PS) on their plasma membrane when propagating coagulation within a developing thrombus. Here the authors show that an adaptor protein 14-3-3 regulates mitochondrial function and PS exposure and thus platelet procoagulant activity, promising a new therapy to reduce thrombosis.
- Simone M. Schoenwaelder
- , Roxane Darbousset
- & Shaun P. Jackson
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Article
| Open AccessA cholinergic-sympathetic pathway primes immunity in hypertension and mediates brain-to-spleen communication
Immune system participates in the development of high blood pressure. Here the authors show that cholinergic-sympathetic pathway mediated by the α7nAChR receptor and the activation of splenic T cells prime immunity during hypertension and that selective splenic denervation protects against the onset of hypertension in mice.
- Daniela Carnevale
- , Marialuisa Perrotta
- & Giuseppe Lembo
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Article
| Open AccessLoss of RNA expression and allele-specific expression associated with congenital heart disease
Congenital heart disease (CHD) is a disorder that occurs in ∼1% of live births. Here the authors describe a genome-wide allele-specific expression analyses in CHD patients, identifying five new genes involved in CHD and showing that paternally-expressed imprinted genes are monoallelic, while maternally-expressed imprinted genes are biallelic.
- David M. McKean
- , Jason Homsy
- & J. G. Seidman
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Article
| Open AccessAn imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques
Atherosclerosis progression is linked to inflammatory processes in the blood vessel wall. Here, the authors show that, with the progression of atherosclerosis, the resolution of inflammation is impaired as the result of an imbalance between specialized pro-resolving lipid mediators and leukotrienes.
- Gabrielle Fredman
- , Jason Hellmann
- & Ira Tabas
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Article
| Open AccessPalmitoyl acyltransferase DHHC21 mediates endothelial dysfunction in systemic inflammatory response syndrome
Breaking down the endothelial barrier is a hallmark of systemic inflammatory response syndrome. Here the authors show that palmitoylation, a post-translational modification of proteins, plays a critical role in altering endothelial function during inflammation, and suggest the targeting of palmitoyl acyltransferase DHHC21 as potential disease therapy.
- Richard S. Beard Jr.
- , Xiaoyuan Yang
- & Sarah Y. Yuan
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Article
| Open AccessNeutralizing blood-borne polyphosphate in vivo provides safe thromboprotection
The inorganic procoagulant polymer polyphosphate participates in thrombosis via factor XII. Here the authors use recombinant probes that specifically bind or degrade circulating polyphosphate to protect mice in arterial and venous thrombosis models without an increased bleeding risk, the primary complication of all currently used anticoagulants.
- Linda Labberton
- , Ellinor Kenne
- & Thomas Renné
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Article
| Open AccessVascular microRNA-204 is remotely governed by the microbiome and impairs endothelium-dependent vasorelaxation by downregulating Sirtuin1
Commensal bacteria, the vast majority of which reside in the gut, are involved in development of many diseases, including atherosclerotic vascular disease. Here the authors show that these bacteria remotely increase expression of vascular microRNA-204, which targets Sirt1 in the endothelium to impair endothelial function.
- Ajit Vikram
- , Young-Rae Kim
- & Kaikobad Irani
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Article
| Open AccessRegulation of monocyte cell fate by blood vessels mediated by Notch signalling
Circulating Ly6Clo monocytes are thought to be derived from Ly6Chi subset. Here the authors show that Notch signalling is activated in Ly6Clocells and is required for their differentiation, and that Notch ligands that initiate this signalling are provided by a subset of endothelial cells.
- Jaba Gamrekelashvili
- , Roberto Giagnorio
- & Florian P. Limbourg
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Article
| Open AccessA strategy to discover new organizers identifies a putative heart organizer
Organizers are regions in the embryo that induce cell fate and impart pattern on neighbouring regions. Here, the authors search for new organizers based on a common gene signature, and show that the Anterior Intestinal Portal endoderm induces cardiac identity, specifies ventricle and inhibits atrial character.
- Claire Anderson
- , Mohsin A. F. Khan
- & Claudio D. Stern