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In vivo model with targeted cAMP biosensor reveals changes in receptor–microdomain communication in cardiac disease
cAMP is a second messenger that acts in distinct intracellular locations regulating diverse cellular functions. Here the authors design a FRET-based cAMP biosensor and use it to measure in vivodynamics of cAMP concentration changes in the sarcoplasmatic reticulum of mouse cardiomyocytes in health and disease.
- Julia U. Sprenger
- , Ruwan K. Perera
- & Viacheslav O. Nikolaev
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| Open AccessIncreased prevalence of EPAS1 variant in cattle with high-altitude pulmonary hypertension
Pulmonary hypertension and congestive right heart failure afflict some cattle living at high altitude in an autosomal dominant pattern, yet no responsible genes have been identified. Here Newman et al.use whole-exome sequencing to identify variants in the hypoxia inducible factor gene, EPAS1.
- John H. Newman
- , Timothy N. Holt
- & Rizwan Hamid
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Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3
The chemical honokiol is found in the bark of magnolia trees, which are used for traditional medicine in Asian countries. Here, Pillai et al, show honokiol protects the heart from hypertrophic remodelling in mice, and even reverses established cardiac hypertrophy, by activating the deacetylase Sirt3.
- Vinodkumar B. Pillai
- , Sadhana Samant
- & Mahesh P. Gupta
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| Open AccessFlavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis
The hepatic enzyme FMO3 has been linked to atherosclerosis. Here the authors show that FMO3 is upregulated in various models of diabetes and link FMO3 with key transcriptional regulators of hepatic glucose and cholesterol synthesis, thus proposing a mechanistic connection between diabetes and atherosclerosis.
- Ji Miao
- , Alisha V. Ling
- & Sudha B. Biddinger
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| Open AccessRGS1 regulates myeloid cell accumulation in atherosclerosis and aortic aneurysm rupture through altered chemokine signalling
Vascular inflammation plays a key role in pathogenesis of major vascular diseases. Here the authors show that Regulator of G-Protein Signaling-1 (RGS1) controls macrophage function in the development of vascular inflammation that underlies atherosclerosis and abdominal aortic aneurysms in mice and humans.
- Jyoti Patel
- , Eileen McNeill
- & Keith M. Channon
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| Open AccessComplement C1q-induced activation of β-catenin signalling causes hypertensive arterial remodelling
The role of macrophages in hypertension-induced arterial remodeling is poorly understood. Here, Sumida et al. show that high blood pressure drives the alternatively activated macrophages to secrete complement C1q protein, which in turn elicits proliferative β-catenin signalling in the arterial smooth muscle cells.
- Tomokazu Sumida
- , Atsuhiko T. Naito
- & Issei Komuro
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| Open AccessA rapid bioluminescence assay for measuring myeloperoxidase activity in human plasma
Levels of the enzyme myeloperoxidase in the blood are considered a biomarker for the severity of cardiovascular disease. Here the authors report a rapid and inexpensive method for measuring myeloperoxidase activity in human plasma by luminescence, after adsorption of the enzyme to a polymer surface.
- Reece J. Goiffon
- , Sara C. Martinez
- & David Piwnica-Worms
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The mitochondrial uniporter controls fight or flight heart rate increases
Animals react to threats by increasing their heart rate. Wu et al. show that mitochondrial calcium uptake via a highly selective ion channel, the mitochondrial calcium uniporter, stimulates metabolism in cardiac pacemaker cells and is essential for physiological pulse acceleration but not resting heart rate.
- Yuejin Wu
- , Tyler P. Rasmussen
- & Mark E. Anderson
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Increased atrial arrhythmia susceptibility induced by intense endurance exercise in mice requires TNFα
Endurance exercise is associated with an increased risk of atrial fibrillation. Here, the authors show the adipokine TNFα is a crucial mediator of exercise-induced atrial fibrillation and irreversible atrial remodelling characterized by fibrosis and inflammation.
- Roozbeh Aschar-Sobbi
- , Farzad Izaddoustdar
- & Peter H. Backx
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Exercise at depth alters bradycardia and incidence of cardiac anomalies in deep-diving marine mammals
Deep-sea diving mammals routinely undergo extreme physiological challenges not experienced by their terrestrial counterparts. Using high-resolution electrocardiographic recorders fitted to seals and dolphins, Williams et al. report an increased frequency of cardiac arrhythmias at greater exercise intensity and dive depth.
- Terrie M. Williams
- , Lee A. Fuiman
- & Randall W. Davis
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| Open AccessThe switching role of β-adrenergic receptor signalling in cell survival or death decision of cardiomyocytes
The contribution of signal strength on cell fate decisions is often not reflected in signalling networks. By combining mathematical simulation and biochemical experiments in cultured adult cardiomyocytes, Shin et al. show that the concentration of a β-adrenergic receptor agonist affects the expression of Bcl-2, influencing the balance between cell survival and death.
- Sung-Young Shin
- , Taeyong Kim
- & Do Han Kim
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Platelets promote tumour metastasis via interaction between TLR4 and tumour cell-released high-mobility group box1 protein
Factors affecting the fate of disseminating tumour cells in the circulation play a critical role in metastasis. Here the authors show that TLR4 on platelets promotes their adhesion to tumour cells and enhances metastasis.
- Le-Xing Yu
- , Lei Yan
- & Hong-Yang Wang
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| Open AccessInterferon regulatory factor 9 is critical for neointima formation following vascular injury
Blood vessels respond to injury by thickening the supportive smooth muscle layer in a process known as neointima formation. Here the authors describe a novel regulatory pathway of neointima formation that involves a transcription factor, Interferon Regulating Factor 9, and its downstream target, the deacetylase SIRT1.
- Shu-Min Zhang
- , Li-Hua Zhu
- & Hongliang Li
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Dynamic GATA4 enhancers shape the chromatin landscape central to heart development and disease
Transcription factors (TFs) drive spatiotemporal patterns of gene expression that control organ development and disease responses. Here, He et al.show that chromatin occupancy of GATA4 varies between fetal, adult and hypertrophic heart to direct developmental stage- and disease-specific transcriptional programs.
- Aibin He
- , Fei Gu
- & William T. Pu
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Megakaryocyte-specific Profilin1-deficiency alters microtubule stability and causes a Wiskott–Aldrich syndrome-like platelet defect
Patients with mutations in the gene encoding the cytoskeleton regulator WAS have platelet defects. Here the authors show that the WAS-binding protein, Profilin1, is essential for platelet formation in mice, and that its deficiency reproduces the bleeding disorder of patients with WAS mutations.
- Markus Bender
- , Simon Stritt
- & Bernhard Nieswandt
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Cardiac arrhythmia induced by genetic silencing of ‘funny’ (f) channels is rescued by GIRK4 inactivation
The ‘funny’ current (If) is important for the generation and regulation of the heart’s automaticity. Here the authors show that If silencing through genetic modification of the f-channel component HCN4 causes heart arrhythmia by altering Ca2+handling in pacemaker myocytes.
- Pietro Mesirca
- , Jacqueline Alig
- & Matteo E. Mangoni
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| Open AccessMyocardium-derived angiopoietin-1 is essential for coronary vein formation in the developing heart
The secreted ligand Angiopoietin-1 is essential for embryonic blood vessel development and adult vascular homeostasis. Here the authors show, using conditional knockout mice, that myocardium-derived Angiopoietin-1 is required for the formation of coronary veins, but not arteries.
- Yoh Arita
- , Yoshikazu Nakaoka
- & Issei Komuro
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| Open AccessIdentification of platelet function defects by multi-parameter assessment of thrombus formation
Platelets from patients with bleeding disorders often display altered adherence to surface proteins. In this study, de Witt et al.design a flow chamber for the systematic interrogation of platelets attaching to 52 adhesive surfaces, which may be helpful for the diagnosis of platelet disorders.
- Susanne M. de Witt
- , Frauke Swieringa
- & Judith M.E.M. Cosemans
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| Open AccessH2S and NO cooperatively regulate vascular tone by activating a neuroendocrine HNO–TRPA1–CGRP signalling pathway
Nitric oxide (NO) and hydrogen sulphide (H2S) are two gaseous signalling molecules produced in tissues. Here the authors propose that NO and H2S react with each other to form nitroxyl (HNO), which activates the TRPA1 channel in nerve cells and triggers the release of the vasoactive peptide CGRP.
- Mirjam Eberhardt
- , Maria Dux
- & Milos R. Filipovic
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Haemodynamic and extracellular matrix cues regulate the mechanical phenotype and stiffness of aortic endothelial cells
Endothelial cells at the inner surface of blood vessels are exposed to mechanical forces as a result of blood flow. Here the authors show that the interaction of extracellular matrix proteins with adhesion molecules on the endothelial cell surface determines cellular stiffness and sensitivity to mechanical forces.
- Caitlin Collins
- , Lukas D. Osborne
- & Ellie Tzima
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MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2
Myocardin-related transcription factors (MRTFs) increase muscle growth and regeneration. Here, Hinkel et al. show that MRTFs also promote microvessel growth and maturation in chronic ischaemic disease of the heart or peripheral muscle by increasing the expression of the pro-angiongenic factors, CCN1 and CCN2.
- Rabea Hinkel
- , Teresa Trenkwalder
- & Christian Kupatt
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Cathepsin K-mediated notch1 activation contributes to neovascularization in response to hypoxia
The cathepsin family of proteases cleaves intracellular as well as extracellular proteins. Here the authors implicate cathepsin K in ischaemia-induced neovascularization by showing that cathepsin K increases the levels of cleaved Notch1 and downstream Notch signalling in endothelial cells.
- Haiying Jiang
- , Xian Wu Cheng
- & Masafumi Kuzuya
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| Open AccessTRPV2 is critical for the maintenance of cardiac structure and function in mice
The TRPV2 calcium channel can be activated by mechanical stretch and may act as a mechanoreceptor in tissues. Here the authors deplete the TRPV2 calcium channel from the hearts of adult mice, showing that TRPV2 is important for the maintenance of cardiac structure and function.
- Yuki Katanosaka
- , Keiichiro Iwasaki
- & Keiji Naruse
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| Open AccessGATA-dependent regulatory switches establish atrioventricular canal specificity during heart development
The atrioventricular canal partitions the developing vertebrate heart. Here, the authors show that the cardiac transcription factor Gata4 together with histone modification enzymes and localized co-factors binds atrioventricular canal-specific enhancers, thereby repressing gene activity in the cardiac chambers.
- Sonia Stefanovic
- , Phil Barnett
- & Vincent M. Christoffels
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Alternative splicing regulates vesicular trafficking genes in cardiomyocytes during postnatal heart development
Alternative splicing is a process during gene expression that increases the diversity of proteins encoded by a single gene. Here, the authors perform RNA-sequencing on cardiac cells from mice and show that extensive changes in gene expression and alternative splicing occur during the first month after birth.
- Jimena Giudice
- , Zheng Xia
- & Thomas A. Cooper
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CARL lncRNA inhibits anoxia-induced mitochondrial fission and apoptosis in cardiomyocytes by impairing miR-539-dependent PHB2 downregulation
The prohibitin complex promotes cell survival by regulating mitochondrial morphogenesis. Wang et al.identify a long non-coding RNA that regulates this complex in cardiomyocytes by acting as a sponge to downregulate a prohibitin-targetting miRNA, protecting cells from apoptosis in anoxic conditions.
- Kun Wang
- , Bo Long
- & Pei-Feng Li
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3D multifunctional integumentary membranes for spatiotemporal cardiac measurements and stimulation across the entire epicardium
Tools for cardiac physiological mapping are important for basic and clinical cardiac research. Here the authors use 3D printing to create a thin, elastic silicone sheath that fits tightly around the entire epicardium and contains sensors to measure a variety of physiological parameters of the beating heart ex vivo.
- Lizhi Xu
- , Sarah R. Gutbrod
- & John A. Rogers
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| Open AccessIRF8 suppresses pathological cardiac remodelling by inhibiting calcineurin signalling
The transcription factor interferon regulatory factor 8 (IRF8) is known to regulate differentiation and function of immune cells. Here the authors show that IRF8 is upregulated in the hypertrophic heart in humans and mice, where it suppresses cardiac remodelling by inhibiting calcineurin signalling.
- Ding-Sheng Jiang
- , Xiang Wei
- & Hongliang Li
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Kctd10 regulates heart morphogenesis by repressing the transcriptional activity of Tbx5a in zebrafish
T-box transcription factors such as Tbx5 have essential roles during cardiac development. Here the authors show that a member of the potassium channel tetramerization domain-containing family, Kctd10 is required for zebrafish heart development and represses the transcriptional activity of Tbx5.
- Xiangjun Tong
- , Yao Zu
- & Bo Zhang
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A Nodal-independent and tissue-intrinsic mechanism controls heart-looping chirality
Nodal signalling has been implicated in the asymmetric positioning of various organs. Here, Noël et al.show that the asymmetry of the embryonic zebrafish heart is also established in the absence of Nodal signalling, suggesting a Nodal-independent mechanism that relies on actomyosin activity.
- Emily S. Noël
- , Manon Verhoeven
- & Jeroen Bakkers
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| Open AccessSox17 is indispensable for acquisition and maintenance of arterial identity
The transcription factor Sox17 is required for the development of the vasculature in vertebrates. Here Corada et al. show that Sox17 acts downstream of Wnt signalling and upstream of Notch signalling in the regulation of artery and vein differentiation in mice.
- Monica Corada
- , Fabrizio Orsenigo
- & Elisabetta Dejana
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Fibroblast growth factor 21 protects against cardiac hypertrophy in mice
Fibroblast growth factor 21 (FGF21) regulates energy metabolism in peripheral tissues. Here Planavila and colleagues show that FGF21 also acts directly on cardiomyocytes, thereby protecting mice against cardiac hypertrophy.
- A. Planavila
- , I. Redondo
- & F. Villarroya
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| Open AccessHaemodynamically dependent valvulogenesis of zebrafish heart is mediated by flow-dependent expression of miR-21
microRNAs rapidly regulate gene expression and are implicated in cardiogenesis and angiogenesis. Banjo and colleagues show that the microRNA mir-21 is activated by the physical forces generated by blood flow, and that this regulates the development of heart valves in zebrafish.
- Toshihiro Banjo
- , Janin Grajcarek
- & Toshihiko Ogura
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| Open AccessVE-PTP regulates VEGFR2 activity in stalk cells to establish endothelial cell polarity and lumen formation
Vascular endothelial growth factor is implicated in blood vessel development. In zebrafish, Hayashi et al. find that blood vessel development is dependent on the suppression of vascular endothelial growth factor by the phosphatase VE-PTP, which is recruited by activation of the angiopoietin receptor Tie2.
- Makoto Hayashi
- , Arindam Majumdar
- & Lena Claesson-Welsh
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Haemogenic endocardium contributes to transient definitive haematopoiesis
Cardiac and endocardial/endothelial cells arise from progenitor cells expressing multiple haematopoietic transcription factors. Nakano and colleagues find that Nkx2–5-positive endocardial cells serve as a de novosource for definitive haematopoietic progenitors during mammalian embryogenesis.
- Haruko Nakano
- , Xiaoqian Liu
- & Atsushi Nakano
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Human haemodynamic frequency harmonics regulate the inflammatory phenotype of vascular endothelial cells
Natural variations in blood flow haemodynamics are associated with localized inflammation and atherosclerosis. Here the authors show that individual harmonics present within this complex signal have distinct impacts on the inflammatory phenotype in endothelial cells.
- Ryan E. Feaver
- , Bradley D. Gelfand
- & Brett R. Blackman
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Preotic neural crest cells contribute to coronary artery smooth muscle involving endothelin signalling
Endothelin-1 regulates cardiovascular development by acting on neural crest cells. Here endothelin-1-deficient mice are studied, revealing that preotic neural crest cells differentiate into coronary artery smooth muscle cells through endothelin-1-dependent mechanisms.
- Yuichiro Arima
- , Sachiko Miyagawa-Tomita
- & Hiroki Kurihara
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Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart
Mice that cannot produce the hormone Klotho show various aging-related phenotypes. Here, Xie and colleagues reveal that Klotho protects the heart of mice from stress-induced remodelling by inhibiting exocytosis of the TRPC6 ion channel in cardiomyocytes.
- Jian Xie
- , Seung-Kuy Cha
- & Chou-Long Huang
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| Open AccessThe miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy
Heart failure is often a consequence of pathological growth of cardiomyocytes or cardiac hypertrophy. Here Ucar and colleagues report that the microRNAs miR-132 and miR-212 promote cardiac hypertrophy and inhibit autophagy in cardiomyocytes by downregulating the transcription factor FoxO3.
- Ahmet Ucar
- , Shashi K. Gupta
- & Thomas Thum
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Real-time in vivo imaging of the beating mouse heart at microscopic resolution
Microscopic imaging techniques have a high spatio-temporal resolution but, in living animals, are hampered by cardiac and respiratory motion. This paper describes a microscopic setup that allows fluorescent confocal imaging of the beating mouse heart over a period of several hours.
- Sungon Lee
- , Claudio Vinegoni
- & Ralph Weissleder
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Differentiation of multipotent vascular stem cells contributes to vascular diseases
De-differentiation and proliferation of vascular smooth muscle cells is thought to have a dominant role in vascular remodelling. Here, Tanget al. identify a new type of multipotent vascular stem cell in the blood vessel wall that contributes to this process, thereby challenging the established hypothesis.
- Zhenyu Tang
- , Aijun Wang
- & Song Li
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Mouse and human strategies identify PTPN14 as a modifier of angiogenesis and hereditary haemorrhagic telangiectasia
Hereditary haemorrhagic telangiectasia (HTT) is caused by mutations in TGFβ/bone morphogenetic protein signalling genes. Here, Benzinouet al. show that variants of PTPN14, a gene within a mouse Tgfb1 modifier locus, associate with pulmonary arteriovenous malformation in HTT patients, shedding light on the molecular aetiology of this disease.
- Michael Benzinou
- , Frederic F. Clermont
- & Rosemary J. Akhurst
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| Open AccessBRCA1 is an essential regulator of heart function and survival following myocardial infarction
The tumour suppressor BRCA1 is mutated in familial breast and ovarian cancer. Now, Shuklaet al.demonstrate that mice lacking BRCA1 in cardiomyocytes are more sensitive to ischaemia than control mice, and that BRCA1 is elevated in human tissues exposed to ischaemia, suggesting a cardioprotective role for BRCA1.
- Praphulla C. Shukla
- , Krishna K. Singh
- & Subodh Verma
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| Open AccessChromatin remodelling complex dosage modulates transcription factor function in heart development
Inherited congenital heart defects are prevalent in the human population, but the molecular mechanisms are poorly understood. In this article, deficiency in the chromatin remodelling factor, Brg1, is shown to alter cardiac development in both mouse and zebrafish laboratory models.
- Jun K. Takeuchi
- , Xin Lou
- & Benoit G. Bruneau