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| Open AccessThe long noncoding RNA lncCIRBIL disrupts the nuclear translocation of Bclaf1 alleviating cardiac ischemia–reperfusion injury
Cardiac ischemia–reperfusion (I/R) injury represents a key threat to human health. This study reveals that the long noncoding RNA lncRNA-CIRBIL is protective against I/R injury by inhibiting the nuclear translocation of Bclaf1.
- Yang Zhang
- , Xiaofang Zhang
- & Zhenwei Pan
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Article
| Open AccessCardiomyocytes stimulate angiogenesis after ischemic injury in a ZEB2-dependent manner
ZEB2 transcription factor is increased in a subset of cardiomyocytes during stress to induce cardioprotective effects after injury. Here the authors show that therapeutic delivery of ZEB2 prevents cardiac dysfunction after ischemic damage and promotes the activation of pro-angiogenic signals.
- Monika M. Gladka
- , Arwa Kohela
- & Eva van Rooij
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Article
| Open AccessQKI is a critical pre-mRNA alternative splicing regulator of cardiac myofibrillogenesis and contractile function
RNA binding protein Quaking (QKI) is known for its broad function in pre-mRNA splicing and modification and its association with several neurodevelopmental disorders. Here the authors reveal that QKI-mediated regulation of RNA splicing is indispensable to cardiac development and contractile physiology.
- Xinyun Chen
- , Ying Liu
- & Ning Sun
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Article
| Open AccessMetavinculin modulates force transduction in cell adhesion sites
Muscle cells express an adhesion molecule called metavinculin, which has been associated with cardiomyopathies. Here, the authors employed molecular tension sensors to reveal that metavinculin expression modulates cell adhesion mechanics and they develop a mouse model to demonstrate that the presence of metavinculin is not as critical for heart muscle function as previously thought.
- Verena Kanoldt
- , Carleen Kluger
- & Carsten Grashoff
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Article
| Open AccessEosinophils improve cardiac function after myocardial infarction
Blood eosinophil (EOS) counts may serve as risk factors for human coronary heart diseases. Here the authors show that increased circulating and myocardial EOS after myocardial infarction play a cardioprotective role by reducing cardiomyocyte death, cardiac fibroblast activation and fibrosis, and endothelium activation-mediated inflammatory cell accumulation.
- Jing Liu
- , Chongzhe Yang
- & Guo-Ping Shi
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| Open AccessA macrophage-specific lncRNA regulates apoptosis and atherosclerosis by tethering HuR in the nucleus
Long non coding RNA molecules have been implicated in the immunopathology of a range of inflammatory pathologies. Here the authors show lncRNA MAARS regulates apoptosis via interaction with HuR in the context of atherosclerosis.
- Viorel Simion
- , Haoyang Zhou
- & Mark W. Feinberg
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Article
| Open AccesscAMP-dependent regulation of HCN4 controls the tonic entrainment process in sinoatrial node pacemaker cells
The involvement of cAMP-dependent regulation of HCN4 in the chronotropic heart rate response is a matter of debate. Here the authors use a knockin mouse model expressing cAMP-insensitive HCN4 channels to discover an inhibitory nonfiring cell pool in the sinoatrial node and a tonic and mutual interaction between firing and nonfiring pacemaker cells that is controlled by cAMP-dependent regulation of HCN4, with implications in chronotropic heart rate responses.
- Stefanie Fenske
- , Konstantin Hennis
- & Christian Wahl-Schott
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Article
| Open AccessInterleukin-1 receptor-induced PGE2 production controls acetylcholine-mediated cardiac dysfunction and mortality during scorpion envenomation
Cardiac dysfunction is a major complication that precedes death after scorpion envenomation. Here, authors show that heart failure and mortality are caused by excessive acetylcholine release, which requires IL-1R-dependent PGE2 production. Dexamethasone treatment effectively inhibits cardiac dysfunction and mortality.
- Mouzarllem B. Reis
- , Fernanda L. Rodrigues
- & Lúcia H. Faccioli
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Article
| Open AccessCHIP phosphorylation by protein kinase G enhances protein quality control and attenuates cardiac ischemic injury
Carboxyl terminus of Hsc70-interacting protein (CHIP) is proteostasis regulator. Here the authors show that CHIP-mediated protein turnover is enhanced by PKG-mediated phosphorylation, which results in attenuated cardiac ischemic proteotoxicity.
- Mark J. Ranek
- , Christian Oeing
- & David A. Kass
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Article
| Open AccessNkx2-5 defines distinct scaffold and recruitment phases during formation of the murine cardiac Purkinje fiber network
Here, the authors apply genetic fate mapping and temporal clonal analysis to study progenitor recruitment and network morphogenesis of murine cardiac Purkinje fibers. Additionally, they characterize how transcription factor dosage regulates cell fate divergence during distinct phases of this process.
- Caroline Choquet
- , Robert G. Kelly
- & Lucile Miquerol
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Article
| Open AccessFetal whole heart blood flow imaging using 4D cine MRI
Three-dimensional imaging of the fetal heart and quantification of blood flow in the surrounding vessels is very challenging because the heart is small and the fetus is free to move in the womb. Here, the authors demonstrate motion-corrected 4D flow MRI of the whole fetal heart and major vessels.
- Thomas A. Roberts
- , Joshua F. P. van Amerom
- & Joseph V. Hajnal
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Article
| Open AccessTranscriptomic profiling of human cardiac cells predicts protein kinase inhibitor-associated cardiotoxicity
Cardiotoxic adverse events associated with kinase inhibitors are a growing concern in clinical oncology. Here the authors use cellular transcriptomic responses of human cardiomyocytes treated with protein kinase inhibitors and the associated drug structural signatures to determine an integrated predictive signature of cardiotoxicity.
- J. G. Coen van Hasselt
- , Rayees Rahman
- & Ravi Iyengar
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Article
| Open AccessIRF1-mediated downregulation of PGC1α contributes to cardiorenal syndrome type 4
The pathogenic mechanisms of cardiorenal syndrome type 4 (CRS4) remain unclear. Here, the authors identify IRF1-PGC1α axis-mediated myocardial energy metabolism remodeling as a contributor to CRS4 pathogenesis, thus providing potential new targets for reducing cardiovascular events in CKD patients.
- Yinghui Huang
- , Shaobo Wang
- & Jinghong Zhao
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Article
| Open AccessAn investigation of causal relationships between prediabetes and vascular complications
Prediabetes has been associated with diabetes complications, but these relationships may be confounded. Here the authors show, using genetic data in causal inference analyses, that prediabetes raises risk of coronary heart disease, but not other diabetes complications.
- Pascal M. Mutie
- , Hugo Pomares-Millan
- & Paul W. Franks
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Article
| Open AccessOntogeny of arterial macrophages defines their functions in homeostasis and inflammation
Arterial macrophages develop from either yolk sac or bone marrow progenitors. Here, the author show that ageing-induced reduction of arterial macrophages is not replenished by bone marrow-derived cells, but under inflammatory conditions circulating monocytes are recruited to maintain homeostasis, while arterial macrophages of yolk sac origin carry out tissue repair.
- Tobias Weinberger
- , Dena Esfandyari
- & Christian Schulz
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Article
| Open AccessMitochondrial CaMKII causes adverse metabolic reprogramming and dilated cardiomyopathy
Little is known about how cardiac metabolism remodels following cardiac injury. Here, the authors show that mitochondrial CaMKII plays an important role in remodeling cardiac metabolism after injury and that replacement of mitochondrial creatine kinase improves energetics and protects against adverse remodeling.
- Elizabeth D. Luczak
- , Yuejin Wu
- & Mark E. Anderson
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Article
| Open AccessChromosome 1q21.2 and additional loci influence risk of spontaneous coronary artery dissection and myocardial infarction
Spontaneous coronary artery dissection (SCAD) is a cause of myocardial infarction Here, the authors present a genome-wide association study of SCAD, finding an association at 1q21.2 which potentially affects expression of ADAMTSL4.
- Jacqueline Saw
- , Min-Lee Yang
- & Santhi K. Ganesh
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Article
| Open AccessCardiac dopamine D1 receptor triggers ventricular arrhythmia in chronic heart failure
The pathophysiological role of dopamine D1 receptor (D1R) in chronic heart failure remains elusive. Here the authors show that D1R-expressing cardiomyocytes appear in chronic heart failure and play a pivotal role in triggering lethal ventricular arrhythmias.
- Toshihiro Yamaguchi
- , Tomokazu S. Sumida
- & Issei Komuro
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Article
| Open AccessTissue sodium excess is not hypertonic and reflects extracellular volume expansion
Na+ has been suggested to accumulate in tissues, particularly skin, in a hypertonic manner and to exert local pathogenic effects. Here, we reappraise this phenomenon which is systemic in nature and reflects isotonic changes in the relative extracellular volume in tissues, e.g. subclinical oedema; as such, it occurs in human hypertension and aging.
- Giacomo Rossitto
- , Sheon Mary
- & Christian Delles
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Article
| Open AccessPolygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions
Genetic variation predisposes to disease via monogenic and polygenic risk variants. Here, the authors assess the interplay between these types of variation on disease penetrance in 80,928 individuals. In carriers of monogenic variants, they show that disease risk is a gradient influenced by polygenic background.
- Akl C. Fahed
- , Minxian Wang
- & Amit V. Khera
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Article
| Open AccessMachine learning-based prediction of acute coronary syndrome using only the pre-hospital 12-lead electrocardiogram
Diagnosing a heart attack requires excessive testing and prolonged observation, which frequently requires hospital admission. Here the authors report a machine learning-based system based exclusively on ECG data that can help clinicians identify 37% more heart attacks during initial screening.
- Salah Al-Zaiti
- , Lucas Besomi
- & Ervin Sejdić
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Article
| Open AccessEnhancing myocardial repair with CardioClusters
Despite recent progress to advance cardiac cell-based therapy for patients, heart failure mortality rivals most cancers. Here, the authors describe an approach to control and pattern 3 distinct human cardiac cell populations to promote superior repair and regeneration after myocardial infarction.
- Megan M. Monsanto
- , Bingyan J. Wang
- & Mark A. Sussman
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| Open AccessAssociations of cardiovascular biomarkers and plasma albumin with exceptional survival to the highest ages
Supercentenarians are approaching the current longevity limit by avoiding or surviving major illness, thus identifying biomarkers for exceptional survival might provide insights into the protection against disease of aging. Here, the authors show low NT-proBNP and high albumin in plasma are the biological correlates of survival to the highest ages.
- Takumi Hirata
- , Yasumichi Arai
- & Nobuyoshi Hirose
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Article
| Open AccessOrthophosphate increases the efficiency of slow muscle-myosin isoform in the presence of omecamtiv mecarbil
Omecamtiv mecarbil is a small molecule effector under clinical trial for the treatment of systolic heart failure. Here the authors define the molecular mechanisms of its inotropic action and find it can increase the efficiency of contraction in muscle fibres when the orthophosphate concentration rises with the beat frequency.
- Serena Governali
- , Marco Caremani
- & Marco Linari
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Article
| Open AccessIron imaging in myocardial infarction reperfusion injury
Restoration of coronary blood flow after a heart attack may lead to reperfusion injury and pathologic iron deposition. Here, the authors perform magnetic susceptibility imaging showing its association with iron in a large animal model of myocardial infarction during wound healing, and showing feasibility in acute myocardial infarction patients undergoing percutaneous coronary intervention.
- Brianna F. Moon
- , Srikant Kamesh Iyer
- & Walter R. Witschey
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Article
| Open AccessMeningeal lymphatics clear erythrocytes that arise from subarachnoid hemorrhage
Extravasated erythrocytes in cerebrospinal fluid (CSF) contribute to the pathogenesis of subarachnoid haemorrhage (SAH). Here, the authors show that meningeal lymphatics drain extravasated erythorcytes and that blockage of this drainage aggravates SAH severity.
- Jinman Chen
- , Linmei Wang
- & Yongjun Wang
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Article
| Open AccessCore functional nodes and sex-specific pathways in human ischaemic and dilated cardiomyopathy
Study of human heart failure is limited by access to human tissue. Here, the authors apply multi-omic screening in human ischaemic and dilated myocardial tissue and matched controls to determine molecular changes common and unique to each aetiology and to reveal differences between male and female hearts.
- Mengbo Li
- , Benjamin L. Parker
- & John F. O’Sullivan
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Article
| Open AccessSingle-cell analysis of murine fibroblasts identifies neonatal to adult switching that regulates cardiomyocyte maturation
How cardiomyocytes mature and what regulates this is unclear. Here, the authors use single-cell analysis to examine how the population of murine cardiac fibroblasts changes during development and affects maturation of cardiomyocytes.
- Yin Wang
- , Fang Yao
- & Li Wang
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Article
| Open AccessFoxO1–Dio2 signaling axis governs cardiomyocyte thyroid hormone metabolism and hypertrophic growth
Disease stress-induced cardiac hypertrophy is a major mechanism of pathological cardiac remodeling. Here, the authors unveil a previously unrecognized role of a FoxO1–Dio2 signaling axis in maladaptive, afterload-induced cardiac hypertrophy and intracellular thyroid hormone homeostasis.
- Anwarul Ferdous
- , Zhao V. Wang
- & Joseph A. Hill
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Article
| Open AccessMulti-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
- Ioanna Ntalla
- , Lu-Chen Weng
- & Patricia B. Munroe
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Article
| Open AccessStructural insights into the inhibition mechanism of human sterol O-acyltransferase 1 by a competitive inhibitor
Sterol O-acyltransferase 1 (SOAT1, also named ACAT1) is an endoplasmic reticulum resident enzyme which catalyzes the esterification of cholesterol to generate cholesteryl esters. Here, authors report cryo-EM structures of human SOAT1 which reveal the binding site of the competitive inhibitor CI-976.
- Chengcheng Guan
- , Yange Niu
- & Lei Chen
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Article
| Open AccessAnalysis of cardiac magnetic resonance imaging in 36,000 individuals yields genetic insights into dilated cardiomyopathy
Structural changes to the left ventricle are characteristic of dilated cardiomyopathy (DCM), a disease for which many rare genetic variants are known. Here, Pirruccello et al. report GWAS of seven cardiac MRI measurements in the left ventricle and describe shared loci and polygenic association with DCM.
- James P. Pirruccello
- , Alexander Bick
- & Krishna G. Aragam
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Article
| Open AccessA single-cell transcriptomic landscape of primate arterial aging
Arterial degeneration, closely associated with cardiovascular diseases, is driven by aging-related vascular cell-specific transcriptomics changes. This study provides a single-cell transcriptomic atlas for senile aortic and coronary arteries and underscores FOXO3A-based the transcriptional network in vasoprotection during aging.
- Weiqi Zhang
- , Shu Zhang
- & Jing Qu
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Article
| Open AccessSGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease
SGLT2 inhibitors, a class of type 2 diabetes medication, reduce cardiovascular events in patients beyond expectation from blood sugar control. Here the authors report a randomized controlled trial showing that SGLT2 inhibitors reduce inflammasome activation in peripheral macrophages, which may contribute to the cardiovascular protection.
- So Ra Kim
- , Sang-Guk Lee
- & Yong-ho Lee
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Article
| Open AccessAging-regulated anti-apoptotic long non-coding RNA Sarrah augments recovery from acute myocardial infarction
Aging induces cardiovascular disease, but which RNA molecules control cardiac aging is poorly understood. Here the authors identified the aging-regulated non-coding RNA Sarrah, which controls cardiomyocyte survival and cardiac function by inducing cardioprotective genes.
- D. Julia Trembinski
- , Diewertje I. Bink
- & Reinier A. Boon
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Article
| Open AccessUsing proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity
Senolytics have the potential to extend healthspan by selectively killing senescent cells (SCs), but senolytics that target Bcl-xl may cause platelet toxicity. Here, the authors generated a Bcl-xl proteolysis-targeting chimera (PROTAC) senolytic, which effectively clears SCs and rejuvenates tissue stem and progenitor cells in naturally aged mice without causing severe thrombocytopenia.
- Yonghan He
- , Xuan Zhang
- & Daohong Zhou
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Article
| Open AccessThe platelet receptor CLEC-2 blocks neutrophil mediated hepatic recovery in acetaminophen induced acute liver failure
The molecular mechanisms that drive irreversible acute liver failure remain poorly characterized. Here, the authors show that the recently discovered platelet receptor CLEC-2 (C-type lectin-like receptor) perpetuates and worsens liver damage during acute liver injury by blocking restorative neutrophil driven inflammation.
- Abhishek Chauhan
- , Lozan Sheriff
- & Patricia F. Lalor
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Article
| Open AccessGenome-wide association studies and Mendelian randomization analyses for leisure sedentary behaviours
Epidemiological studies have shown an association between sedentary behaviours and cardiovascular disease risk. Here, van de Vegte et al. perform GWAS for self-reported sedentary behaviours (TV watching, computer use, driving) and Mendelian randomization analyses to explore potential causal relationships with coronary artery disease.
- Yordi J. van de Vegte
- , M. Abdullah Said
- & Niek Verweij
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Article
| Open AccessChronic activation of hexosamine biosynthesis in the heart triggers pathological cardiac remodeling
Metabolic remodeling plays an important role in pathological cardiac hypertrophy. Here, the authors show that hexosamine biosynthetic pathway is elevated in the heart by pressure overload, which contributes to heart failure by persistent activation of mTOR.
- Diem Hong Tran
- , Herman I. May
- & Zhao V. Wang
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Article
| Open AccessAutomatic diagnosis of the 12-lead ECG using a deep neural network
The role of automatic electrocardiogram (ECG) analysis in clinical practice is limited by the accuracy of existing models. In that context, the authors present a Deep Neural Network (DNN) that recognizes different abnormalities in ECG recordings which matches or outperform cardiology and emergency resident medical doctors.
- Antônio H. Ribeiro
- , Manoel Horta Ribeiro
- & Antonio Luiz P. Ribeiro
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Article
| Open AccessRemodeling of active endothelial enhancers is associated with aberrant gene-regulatory networks in pulmonary arterial hypertension
Pulmonary arterial hypertension (PAH) is a heterogeneous disease, causing severe breathing problems and cardiac morbidity. Here, the authors study chromatin marks in pulmonary arterial endothelial cells from PAH patients and controls and find changes in transcription factor and enhancer activity that suggest an aberrant response to signalling in PAH.
- Armando Reyes-Palomares
- , Mingxia Gu
- & Judith B. Zaugg
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Article
| Open AccessGating mechanism of hyperpolarization-activated HCN pacemaker channels
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are essential for rhythmic activity in the heart and brain. Here authors reverse the voltage dependence of HCN channels by mutating only two residues located at the interface between the voltage sensor and the pore domain.
- Rosamary Ramentol
- , Marta E. Perez
- & H. Peter Larsson
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Article
| Open AccessRed blood cell-derived semaphorin 7A promotes thrombo-inflammation in myocardial ischemia-reperfusion injury through platelet GPIb
Reperfusion injury following myocardial ischemia is aggravated by inflammation and platelet–neutrophil complex formation. Here the authors show that semaphorin 7A binds to platelet GPIb, enhancing platelet–neutrophil interaction and increasing post-ischemic myocardial tissue injury, and that blockage of semaphorin 7A is protective.
- David Köhler
- , Tiago Granja
- & Peter Rosenberger
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Article
| Open AccessIdentification of two major autoantigens negatively regulating endothelial activation in Takayasu arteritis
Autoantibodies against endothelium have been recognized in Takayasu arteritis (TAK). Here the authors identify endothelial protein C receptor and scavenger receptor class B type 1 as major autoantigens in TAK, and find autoantibodies inhibit the negative regulation of endothelial activation.
- Tomoyuki Mutoh
- , Tsuyoshi Shirai
- & Hiroshi Fujii
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Article
| Open AccessTherapeutic potential of KLF2-induced exosomal microRNAs in pulmonary hypertension
Pulmonary arterial hypertension is a severe lung disease characterised by progressive vascular remodelling. Here, the authors show that reduced signalling of flow-activated transcription factor KLF2 is a common feature of human PAH and that KLF2-regulated exosomal miRNAs have a therapeutic effect.
- Hebah A. Sindi
- , Giusy Russomanno
- & Beata Wojciak-Stothard
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Article
| Open AccessB38-CAP is a bacteria-derived ACE2-like enzyme that suppresses hypertension and cardiac dysfunction
The enzyme ACE2 is involved in cardiac pathology and can counteract heart failure and other cardio-pulmonary diseases. Here the authors show that bacteria produce an ACE2-like enzyme that is effective in suppressing cardiac hypertrophy and fibrosis in mice.
- Takafumi Minato
- , Satoru Nirasawa
- & Keiji Kuba
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Article
| Open AccessInhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers
Cardiovascular calcification is a serious pathology for which effective pharmacological treatments are lacking. Here the authors show that an optimized oligo(ethylene glycol) derivative of inositol phosphate interferes with calcium phosphate crystallization and inhibits soft tissue calcification in vivo following subcutaneous injection.
- Antonia E. Schantl
- , Anja Verhulst
- & Jean-Christophe Leroux
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Article
| Open AccessPreclinical development of a miR-132 inhibitor for heart failure treatment
miR-132 was shown to drive pathological cardiac remodeling, a hallmark of heart failure. Here, the authors show that an antisense inhibitor of miR-132 has favourable pharmacokinetics, safety-tolerability and preclinical efficacy in mouse and porcine models of heart failure.
- Ariana Foinquinos
- , Sandor Batkai
- & Thomas Thum
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Article
| Open AccessMacrophages directly contribute collagen to scar formation during zebrafish heart regeneration and mouse heart repair
Macrophages mediate the fibrotic response after a heart attack by extracellular matrix turnover and cardiac fibroblasts activation. Here the authors identify an evolutionarily-conserved function of macrophages that contributes directly to the forming post-injury scar through cell-autonomous deposition of collagen.
- Filipa C. Simões
- , Thomas J. Cahill
- & Paul R. Riley