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| Open AccessMitochondria are secreted in extracellular vesicles when lysosomal function is impaired
Mitochondrial quality control is critical for cellular homeostasis and survival. Here, the authors identify that defective mitochondria can be eliminated via secretion in large extracellular vesicles when internal lysosomal degradation is compromised.
- Wenjing Liang
- , Shakti Sagar
- & Åsa B. Gustafsson
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Article
| Open AccessIRX2 regulates angiotensin II-induced cardiac fibrosis by transcriptionally activating EGR1 in male mice
Cardiac fibrosis is a common feature of chronic heart failure, and the mechanisms of cardiac fibrosis are unclear. Here, the authors show that iroquois homeobox 2 (IRX2) regulates the early growth response factor 1 (EGR1) pathway upon fibrotic stimulation and drives cardiac fibrosis.
- Zhen-Guo Ma
- , Yu-Pei Yuan
- & Qi-Zhu Tang
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Article
| Open AccessMTH1 protects platelet mitochondria from oxidative damage and regulates platelet function and thrombosis
MTH1 hydrolyzes oxidized nucleotides to prevent their mis-incorporation into DNA under oxidative stress. Here, the authors show that MTH1 is expressed in platelets and its deficiency increases mitochondrial DNA oxidative damage, impairs platelet function and hemostasis.
- Yangyang Ding
- , Xiang Gui
- & Jianlin Qiao
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Article
| Open AccessStructural basis of agonist specificity of α1A-adrenergic receptor
α1-adrenergic receptors (α1- AR) play critical roles in the cardiovascular and nervous systems. Here, the authors report molecular insights into the mechanisms underlying the discrimination between α1A-AR and α1B-AR by the agonist A61603.
- Minfei Su
- , Jinan Wang
- & Xin-Yun Huang
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Article
| Open AccessCardiomyocyte proliferation is suppressed by ARID1A-mediated YAP inhibition during cardiac maturation
Cardiac regeneration is hindered by the limited division of cardiomyocytes. Here, the authors show that Arid1a drives maturation and limits proliferation through interaction with Yap. Suppression of Arid1a enhances proliferation after injury.
- Cornelis J. Boogerd
- , Ilaria Perini
- & Eva van Rooij
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Article
| Open AccessNon-invasive electromechanical assessment during atrial fibrillation identifies underlying atrial myopathy alterations with early prognostic value
Electromechanical characterization during atrial fibrillation (AF) remains a significant gap in the understanding of AF-related atrial myopathy. Here, the authors use non-invasive atrial electromechanical assessment during AF to identify early remodeling changes associated with underlying myopathy, which in the clinic decrease the probability of acute and mid-term successful rhythm control.
- Daniel Enríquez-Vázquez
- , Jorge G. Quintanilla
- & David Filgueiras-Rama
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Article
| Open AccessA flexible optoacoustic blood ‘stethoscope’ for noninvasive multiparametric cardiovascular monitoring
Cardiovascular disease diagnosis can be invasive and complex. Here, the authors present a flexible optoacoustic blood ‘stethoscope’ that noninvasively and continuously monitors cardiovascular health.
- Haoran Jin
- , Zesheng Zheng
- & Yuanjin Zheng
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Article
| Open AccessGenetic insights into resting heart rate and its role in cardiovascular disease
The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke.
- Yordi J. van de Vegte
- , Ruben N. Eppinga
- & Pim van der Harst
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Article
| Open AccessGenetic inhibition of CARD9 accelerates the development of atherosclerosis in mice through CD36 dependent-defective autophagy
Previous studies suggested a role for CARD9 pathway in atherosclerosis but the underlying mechanisms remain poorly understood. Here, the authors show that the pro-atherogenic effects of Card9 deficiency are mediated by CD36-dependent defective autophagy that can be reversed by rapamycin and metformin.
- Yujiao Zhang
- , Marie Vandestienne
- & Hafid Ait-Oufella
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Article
| Open AccessLysophosphatidylserine induces necrosis in pressure overloaded male mouse hearts via G protein coupled receptor 34
iPLA2β produces lipid mediators and induces nuclear shrinkage in caspase-independent cell death. Here, the authors show that lysophosphatidylserine generated by iPLA2β induces necrotic cardiomyocyte death mediated through GPR34 in pressure-overloaded mouse hearts, leading to cardiac dysfunction.
- Ryuta Sugihara
- , Manabu Taneike
- & Kinya Otsu
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Article
| Open AccessCysteines 1078 and 2991 cross-linking plays a critical role in redox regulation of cardiac ryanodine receptor (RyR)
Oxidation of ryanodine receptor calcium channels play a critical role in the onset of many cardiac diseases. Here, authors identify specific amino acids that cause ryanodine receptor malfunction during oxidative stress.
- Roman Nikolaienko
- , Elisa Bovo
- & Aleksey V. Zima
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Article
| Open AccessEzh2 emerges as an epigenetic checkpoint regulator during monocyte differentiation limiting cardiac dysfunction post-MI
Modulating pro-inflammatory immune cell kinetics after myocardial infarction is a critical step to prevent heart dysfunction. In this study, the authors show that Ezh2 pharmacological inhibition, acting as an epigenetic checkpoint in monocytes and macrophages, prevents myocardial infarction-induced cardiac dysfunction.
- Julie Rondeaux
- , Déborah Groussard
- & Sylvain Fraineau
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Article
| Open AccessMacrophage-to-endothelial cell crosstalk by the cholesterol metabolite 27HC promotes atherosclerosis in male mice
Hypercholesterolemia and vascular inflammation both contribute to the pathogenesis of atherosclerosis, but how hypercholesterolemia initiates vascular inflammation is not fully understood. Here the authors report that crosstalk between macrophages and endothelial cells mediated by the cholesterol metabolite 27-hydroxycholesterol drives vascular inflammation and contributes to atherosclerosis in male mice.
- Liming Yu
- , Lin Xu
- & Philip W. Shaul
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Article
| Open AccessNuclear translocation of mitochondrial dehydrogenases as an adaptive cardioprotective mechanism
Chemotherapy can cause severe damage to cardiomyocytes in some patients but it is unclear how cardiomyocytes protect themselves against such stress. Here the authors show that cardiomyocytes initiate an endogenous protective response when exposed to chemotherapeutic agents by translocating mitochondrial enzymes to the nucleus.
- Shubhi Srivastava
- , Priyanka Gajwani
- & Jalees Rehman
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Article
| Open AccessMislocalization of pathogenic RBM20 variants in dilated cardiomyopathy is caused by loss-of-interaction with Transportin-3
The authors show that loss-of-interaction with the nuclear importer, TNPO3, causes cytoplasmic mislocalization of RBM20 variants linked to severe cases of dilated cardiomyopathy. Restoring their nuclear localization alleviates the disease phenotype.
- Julia Kornienko
- , Marta Rodríguez-Martínez
- & Lars M. Steinmetz
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Article
| Open AccessGenome-wide association analysis and Mendelian randomization proteomics identify drug targets for heart failure
Here, the authors perform a large-scale meta-analysis of genome-wide association studies and cis-MR proteomics to identify protein biomarkers and drug targets for heart failure.
- Danielle Rasooly
- , Gina M. Peloso
- & Juan P. Casas
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Article
| Open AccessHighly efficient platelet generation in lung vasculature reproduced by microfluidics
Highly efficient generation of platelets in the vasculature. Here, Zhao et al. show that the mouse platelet precursor cell, megakaryocytes, generate physiological numbers of functional platelets when passaged repeatedly through pulmonary vasculature.
- Xiaojuan Zhao
- , Dominic Alibhai
- & Alastair W. Poole
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Article
| Open AccessAcute stress induces long-term metabolic, functional, and structural remodeling of the heart
Takotsubo disease, a stress induced cardiomyopathy mimicking acute coronary syndrome, increases the risk of heart failure and cardiac death. The authors show here that heart function and structure keep on deteriorating continuously after a single acute stress, this snowball effect being triggered by abnormalities incardiac metabolism.
- Thulaciga Yoganathan
- , Mailyn Perez-Liva
- & Bertrand Tavitian
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Article
| Open AccessStriated muscle-specific base editing enables correction of mutations causing dilated cardiomyopathy
Dilated cardiomyopathy is the second most common cause for heart failure. Here the authors combine CRISPR base editors with the muscle-targeting viral vector AAVMYO to repair patient mutations in the cardiac splice factor Rbm20 in two mouse models.
- Markus Grosch
- , Laura Schraft
- & Lars M. Steinmetz
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Article
| Open AccessSERCA2 phosphorylation at serine 663 is a key regulator of Ca2+ homeostasis in heart diseases
Despite advances in cardioprotection, new therapeutic strategies precluding ischemia-reperfusion injury of patients are still needed. Here, the authors show that preventing serine 663 phosphorylation of SERCA2, significantly increases its activity and protects against cell death, by counteracting cytosolic and mitochondrial Ca2+ overload.
- Fabrice Gonnot
- , Laura Boulogne
- & Ludovic Gomez
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Article
| Open AccessCargo-free particles divert neutrophil-platelet aggregates to reduce thromboinflammation
Platelet-neutrophil aggregates are a hallmark of thromboinflamation. Here, the authors use cargo-free particles to block platelet-neutrophil aggregates’ vascular wall adhesion, which could become an effective thromboinflammation therapy, regardless of disease cause.
- Alison L. Banka
- , M. Valentina Guevara
- & Omolola Eniola-Adefeso
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Article
| Open AccessIDH3γ functions as a redox switch regulating mitochondrial energy metabolism and contractility in the heart
Protein targets that are affected by ROS and underly impaired inotropic effects in the heart are largely unknown. Here, the authors identify the γ-subunit of IDH3 as a redox switch linking oxidative stress to impaired metabolism and heart function.
- Maithily S. Nanadikar
- , Ana M. Vergel Leon
- & Dörthe M. Katschinski
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Article
| Open AccessExtracellular vesicles engineering by silicates-activated endothelial progenitor cells for myocardial infarction treatment in male mice
Extracellular vesicle therapy has shown great potential for the treatment of myocardial infarction. Here, the authors show a silicate biomaterials-based approach to engineer extracellular vesicles from endothelial progenitor cells with high yield and bioactivity for treating myocardial infarction.
- Bin Yu
- , Hekai Li
- & Caiwen Ou
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Article
| Open AccessEndothelial FAT1 inhibits angiogenesis by controlling YAP/TAZ protein degradation via E3 ligase MIB2
The authors report that endothelial protocadherin FAT1 inhibits endothelial proliferation and angiogenesis by promoting degradation of the transcriptional cofactors YAP and TAZ by direct interaction with the E3 ubiquitin ligase Mind Bomb-2 (MIB2).
- Rui Li
- , Jingchen Shao
- & Stefan Offermanns
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Article
| Open AccessEndothelial deletion of PTBP1 disrupts ventricular chamber development
Alternative splicing crucially affects various biological processes, however, its function in heart development is largely unknown. Here, the authors show an essential role of alternative splicing factor PTBP1 in ventricular chamber development.
- Hongyu Liu
- , Ran Duan
- & Yi-Han Chen
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Article
| Open AccessSingle-cell analysis of peripheral blood from high-altitude pulmonary hypertension patients identifies a distinct monocyte phenotype
Single cell transcriptomic sequencing (scRNA) can identify genes that are differentially expressed in cell populations in specific diseases. Here the authors perform scRNA sequencing in a high-altitude pulmonary hypertension (HAPH) cohort and show transcriptional differences in monocyte populations.
- Xin-Hua Wu
- , Yang-Yang He
- & Zhi-Cheng Jing
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Article
| Open AccessConserved transcription factors promote cell fate stability and restrict reprogramming potential in differentiated cells
Transdifferentiation has been proposed as an approach for regenerative medicine, but the mechanisms that safeguard cell identity are not well established. Here they identify transcription factors that oppose transdifferentiation and show that knockdown of these genes improves recovery after myocardial infarction.
- Maria A. Missinato
- , Sean Murphy
- & Alexandre R. Colas
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Article
| Open AccessA defect in mitochondrial protein translation influences mitonuclear communication in the heart
The heart requires high levels of mitochondria to sustain function, and mitochondrial stressors can be transmitted to the nucleus and reprogram metabolism. Here, the authors show that a mitochondrial ribosomal protein is important for heart development in mice by increasing nuclear Klf15 expression.
- Feng Gao
- , Tian Liang
- & Jinghai Chen
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Article
| Open AccessClinical and genetic associations of deep learning-derived cardiac magnetic resonance-based left ventricular mass
A genome-wide association study of cardiac magnetic resonance-derived left ventricular mass index including 43,000 UK Biobank participants reveals 12 associations (11 novel), implicating genes involved in cardiac contractility and cardiomyopathy.
- Shaan Khurshid
- , Julieta Lazarte
- & Steven A. Lubitz
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| Open AccessSingle-cell transcriptomics uncovers a non-autonomous Tbx1-dependent genetic program controlling cardiac neural crest cell development
Cardiac neural crest must differentiate and migrate correctly to achieve proper cardiovascular development. Here, the authors use single cell analyses to show how these cells are altered non-autonomously by loss of Tbx1, the major gene for 22q11.2 deletion syndrome.
- Christopher De Bono
- , Yang Liu
- & Bernice E. Morrow
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Article
| Open AccessVariations in the poly-histidine repeat motif of HOXA1 contribute to bicuspid aortic valve in mouse and zebrafish
Bicuspid aortic valve (BAV) is the most common cardiac defect and although highly heritable, few causal mutations have been identified. Here, the authors identify variants in the poly-histidine repeat motif of HOXA1 and show that its disruption leads to BAV in mice.
- Gaëlle Odelin
- , Adèle Faucherre
- & Stéphane Zaffran
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Article
| Open AccessFibroblast growth factor 18 alleviates stress-induced pathological cardiac hypertrophy in male mice
Although the role of FGFs in cardiovascular disease has attracted extensive attention, the potential role of FGF18 in pathological cardiac hypertrophy remains unknown. Here, the authors show the cardioprotective effect of FGF18 is mediated by maintaining redox homeostasis through FYN/Nox4 signaling.
- Gen Chen
- , Ning An
- & Xu Wang
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Article
| Open AccessRetinol dehydrogenase 10 reduction mediated retinol metabolism disorder promotes diabetic cardiomyopathy in male mice
The current challenges for diabetic cardiomyopathy (DCM) are unclear mechanisms and no effective therapy in clinics. Here, the authors found that the decrease of cardiac retinol dehydrogenase 10 in type 2 diabetes leads to retinol metabolism disorder, cardiac lipid toxicity and cardiomyopathy development, suggesting that correcting the imbalance of cardiac retinol metabolism may be an effective strategy for the treatment of DCM.
- Yandi Wu
- , Tongsheng Huang
- & Weibin Cai
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Article
| Open AccessTransgenic NADH dehydrogenase restores oxygen regulation of breathing in mitochondrial complex I-deficient mice
Activation of breathing during hypoxia is abolished in mice lacking mitochondrial complex I in carotid body chemoreceptors, however the specific contribution of mitochondrial complex I to this process is unclear. Here, the authors show that recovery of NADH dehydrogenase activity, but not proton pumping, by transgenic expression of a yeast enzyme rescues cellular and systemic sensitivity to changes in O2 tension.
- Blanca Jiménez-Gómez
- , Patricia Ortega-Sáenz
- & José López-Barneo
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Article
| Open AccessReproducing extracellular matrix adverse remodelling of non-ST myocardial infarction in a large animal model
The study of the pathophysiology and possible interventions for non-ST-segment elevation myocardial infarction is hindered by the lack of a reproducible pre-clinical model. Here, authors develop an ovine model to reproduce post-ischemic remodeling in non-ST myocardial infarction and reveal distinct complex sugar moieties in cellular membranes and extracellular matrix patterns in infarcted tissue.
- Paolo Contessotto
- , Renza Spelat
- & Mark Da Costa
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Article
| Open AccessThe KLF7/PFKL/ACADL axis modulates cardiac metabolic remodelling during cardiac hypertrophy in male mice
Myocardial substrate metabolism in cardiac hypertrophy or heart failure shifts from fatty acid oxidation to a greater reliance on glycolysis. Here, the authors show that KLF7 can simultaneously regulate key enzymes in glycolysis and fatty acid oxidation to mitigate metabolic imbalance during cardiac hypertrophy.
- Cao Wang
- , Shupei Qiao
- & Weiming Tian
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Article
| Open AccessGSDME-mediated pyroptosis promotes the progression and associated inflammation of atherosclerosis
Macrophages have been shown to have an important function in atherosclerosis. Here the authors show that, in human atherosclerotic plaques and mouse models, GSDME and pyroptosis promote atherosclerosis and inhibition of these pathways could reduce pathology associated with atherosclerotic disease.
- Yuanyuan Wei
- , Beidi Lan
- & Yue Wu
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Article
| Open AccessMolecular mechanisms of coronary artery disease risk at the PDGFD locus
Genes encode risk for coronary disease, identifying how they function is critical to developing new therapies. In work reported the authors have identified one culprit gene, PDGFD, and studied how it functions to promote disease risk.
- Hyun-Jung Kim
- , Paul Cheng
- & Thomas Quertermous
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Article
| Open AccessSVEP1 is an endogenous ligand for the orphan receptor PEAR1
SVEP1 is linked to numerous human diseases, though its disease-promoting mechanism has remained unclear. Here, the authors identify SVEP1 as a ligand for the orphan receptor PEAR1 and provide insight into the role of this interaction in cardiovascular disease.
- Jared S. Elenbaas
- , Upasana Pudupakkam
- & Nathan O. Stitziel
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Article
| Open AccessAngiotensin-converting enzyme inhibitor promotes angiogenesis through Sp1/Sp3-mediated inhibition of notch signaling in male mice
ACE inhibitors are widely used to treat cardiovascular diseases and promote angiogenesis. Here, the authors show a central role for endothelial USP7-Sp1/Sp3-Notch1 signalling in pathophysiological angiogenesis in response to ACE inhibitor treatment.
- Hanlin Lu
- , Peidong Yuan
- & Wencheng Zhang
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Article
| Open AccessVGLL3 is a mechanosensitive protein that promotes cardiac fibrosis through liquid–liquid phase separation
Heart fibrosis involves a feedback loop where stiffening increases fibrosis-related gene expression in myofibroblasts. Here authors reveal the mechanosensitive nuclear translocation of VGLL3, where it phase separates and promotes collagen production, and show that its knock-out is protective after myocardial infarction.
- Yuma Horii
- , Shoichi Matsuda
- & Michio Nakaya
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Article
| Open AccessMultiple pkd and piezo gene family members are required for atrioventricular valve formation
Cardiac valves are essential for heart function, and blood flow stimulation is critical for their formation. Here, researchers have identified a set of mechanosensory genes of the pkd and piezo families as key regulators of valve development.
- Thomas Juan
- , Agatha Ribeiro da Silva
- & Didier Y. R. Stainier
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Article
| Open AccessSingle-cell transcriptomic analysis identifies murine heart molecular features at embryonic and neonatal stages
A detailed multi-staged single cell atlas of heart development could improve our understanding of cell type diversification during cardiac development. Here, the authors generated a large dataset with cells from embryonic and neonatal hearts to identify the stage and chamber specific features in heart development.
- Wei Feng
- , Abha Bais
- & Guang Li
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Article
| Open AccessGenetic architecture of heart failure with preserved versus reduced ejection fraction
While the genetic basis of heart failure has been explored by genetic studies, the differences between subtypes are not well understood. Here, the authors performed genetic analyses on the two major subtypes of heart failure in a large biobank with genetic and health record data, finding unique genetic architecture for each subtype.
- Jacob Joseph
- , Chang Liu
- & Yan V. Sun
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Article
| Open AccessActivation of a transient progenitor state in the epicardium is required for zebrafish heart regeneration
The epicardium supports heart regeneration, though precisely how is unclear. Here the authors define an activated epicardial progenitor population as the source of essential cell types and paracrine factors for successful heart regeneration in zebrafish.
- Yu Xia
- , Sierra Duca
- & Jingli Cao
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Article
| Open AccessPhenome-wide association study of loci harboring de novo tandem repeat mutations in UK Biobank exomes
In UK Biobank exomes, the authors identified de novo mutations in tandem repeat loci. On the population level, these tandem repeats confer large effects on several trait domains including biomarkers, anthropometrics, and tissue microstructures.
- Frank R. Wendt
- , Gita A. Pathak
- & Renato Polimanti
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Article
| Open AccessTargeting cardiomyocyte ADAM10 ectodomain shedding promotes survival early after myocardial infarction
Therapeutic interference with the immune response after myocardial infarction holds the potential to close a clinically relevant gap. Here, the authors show that inhibition of a cardiomyocyte-specific ADAM10 / CX3CL1 axis improves post infarction survival and cardiac function by attenuating neutrophil-mediated myocardial damage.
- Erik Klapproth
- , Anke Witt
- & Ali El-Armouche
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Article
| Open AccessExtracellular traps from activated vascular smooth muscle cells drive the progression of atherosclerosis
Vascular smooth muscle cells (VSMCs) are known for their fate plasticity in atherosclerosis plaque progression. Here, Zhai et al. show that extracellular traps generated from CD68 + VSMCs adversely contribute to plaque progression and highlight their unexpected role in plaque stability by regulating the direction of VSMC trans-differentiation.
- Ming Zhai
- , Shiyu Gong
- & Wenhui Peng
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Article
| Open AccessGPR174 knockdown enhances blood flow recovery in hindlimb ischemia mice model by upregulating AREG expression
Gpr174 is a regulator of regulatory T cells, which play an important role in angiogenesis after hindlimb ischemia. Here, the authors show GPR174-deficient Tregs promote AREG expression by inhibiting Gαs/cAMP/PKA signal pathway and increasing EGR1 nuclear accumulation to improve angiogenesis and vascular remodeling in response to ischemic injury.
- Jin Liu
- , Lihong Pan
- & Aijun Sun