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| 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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| 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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| 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
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Article
| Open AccessDOT1L regulates chamber-specific transcriptional networks during cardiogenesis and mediates postnatal cell cycle withdrawal
How and whether histone modifications regulate distinct gene networks remains insufficiently understood. Here Cattaneo et al show that DOT1L catalyzed H3K79me2 regulates fetal chamber-specific gene expression and neonatal cardiomyocyte cell cycle withdrawal to coordinate heart development.
- Paola Cattaneo
- , Michael G. B. Hayes
- & Sylvia M. Evans
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Article
| Open AccessThe E3 ubiquitin ligase WWP2 regulates pro-fibrogenic monocyte infiltration and activity in heart fibrosis
Non-ischemic cardiomyopathy is a severe disease, characterized by interstitial fibrosis in the left ventricle of the heart. Here authors show that the E3 ubiquitin ligase WWP2 plays a pathogenic role in heart fibrosis via regulating a distinct monocyte population that initiates the process.
- Huimei Chen
- , Gabriel Chew
- & Enrico Petretto
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Article
| Open AccessThrombosis and thrombocytopenia after vaccination against and infection with SARS-CoV-2 in the United Kingdom
Population-based studies can provide information on the safety of COVID-19 vaccines. Here the authors report the rates thrombosis and thrombocytopenia after vaccination against and infection with SARS-CoV-2 in the United Kingdom and compare them with the background (expected) rates in the general population.
- Edward Burn
- , Xintong Li
- & Daniel Prieto-Alhambra
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Article
| Open AccessA non-coding GWAS variant impacts anthracycline-induced cardiotoxic phenotypes in human iPSC-derived cardiomyocytes
Germline variants may pre-dispose patients to an increased risk of developing anthracycline-induced cardiotoxicity. This report provides insights into the mechanism by which a common genetic variant, rs28714259, may confer an increased risk of cardiac damage.
- Xi Wu
- , Fei Shen
- & Bryan Paul Schneider
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Article
| Open AccessMETTL14 is required for exercise-induced cardiac hypertrophy and protects against myocardial ischemia-reperfusion injury
The benefit of regular exercise on the heart has been well documented but the role of RNA m6A modification in exercise-induced cardiac remodelling remains largely unknown. In this study, the authors report that METTL14 plays an important role in RNA m6A modification in exercise-induced physiological cardiac hypertrophy.
- Lijun Wang
- , Jiaqi Wang
- & Junjie Xiao
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Article
| Open AccessDusp6 deficiency attenuates neutrophil-mediated cardiac damage in the acute inflammatory phase of myocardial infarction
Dusp6, an ERK specific phosphatase, was identified as a regenerative repressor during zebrafish heart regeneration. Here, the authors show that Dusp6 deficiency improves post infarctional cardiac repair by predominantly attenuating neutrophil-mediated myocardial damage in mammalian hearts.
- Xiaohai Zhou
- , Chenyang Zhang
- & Jing-Wei Xiong
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Article
| Open AccessMitochondrial Fission Process 1 controls inner membrane integrity and protects against heart failure
Mitochondria power the beating heart. Here, Donnarumma et al. show that loss of the inner mitochondrial membrane protein MTFP1 in cardiomyocytes reduces bioenergetic efficiency and cell death resistance leading to heart failure in mice.
- Erminia Donnarumma
- , Michael Kohlhaas
- & Timothy Wai
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| Open Access2′–5′ oligoadenylate synthetase‑like 1 (OASL1) protects against atherosclerosis by maintaining endothelial nitric oxide synthase mRNA stability
Maintaining optimal eNOS levels is important during cardiovascular events, although little is known regarding the mechanism of eNOS protection. Here, the authors show a regulatory role of endothelial OASL1 in maintaining eNOS mRNA stability and vascular biology under atheroprone conditions.
- Tae Kyeong Kim
- , Sejin Jeon
- & Goo Taeg Oh
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Article
| Open AccessJAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm
JAK2V617F mutation is associated with an increased risk for athero-thrombotic cardiovascular disease, but its role in aortic disease development remains unknown. Here, the authors show that JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm.
- Rida Al-Rifai
- , Marie Vandestienne
- & Hafid Ait-Oufella
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Article
| Open AccessHIF1α-AS1 is a DNA:DNA:RNA triplex-forming lncRNA interacting with the HUSH complex
Using a composite bioinformatics approach, the DNA:DNA:RNA triplex-forming lncRNAs HIF1α-AS1 was identified in human endothelial cells which recruits an epigenetic silencing complex to limit expression of triplex target genes.
- Matthias S. Leisegang
- , Jasleen Kaur Bains
- & Ralf P. Brandes
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Article
| Open AccessMyocardial TRPC6-mediated Zn2+ influx induces beneficial positive inotropy through β-adrenoceptors
Baroreflex control of cardiac contractility is essential to maintain cardiocirculatory homeostasis. Here, Oda et al show that α1 adrenoceptor-stimulated Zn2+ entry through TRPC6 channels boosts β adrenoceptor-dependent myocardial positive inotropy.
- Sayaka Oda
- , Kazuhiro Nishiyama
- & Motohiro Nishida
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Article
| Open AccessKynurenine promotes neonatal heart regeneration by stimulating cardiomyocyte proliferation and cardiac angiogenesis
Failed cardiac regeneration to repair adult acute myocardial ischemia is the leading cause of heart failure. Here, the authors show that IDO1-derived kynurenine metabolism promotes cardiomyocyte proliferation and cardiac angiogenesis via cytoplasmic aryl hydrocarbon receptor (AhR) and nucleic AhR translocation signalling.
- Donghong Zhang
- , Jinfeng Ning
- & Ming-Hui Zou
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Article
| Open AccessE-cigarettes and their lone constituents induce cardiac arrhythmia and conduction defects in mice
The use of E-cigarettes has increased despite the unknown long-term effects. Here the authors show that e-cigarette aerosols alter cardiac conduction, repolarization, and autonomic regulation in mice, contingent on the chemical composition of e-liquids and partly through parasympathetic modulation.
- Alex P. Carll
- , Claudia Arab
- & Daniel J. Conklin
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Article
| Open AccessNIMA-related kinase 9 regulates the phosphorylation of the essential myosin light chain in the heart
Phosphorylation of the essential myosin light chain (ELC) influence actin-myosin crossbridge cycling in the heart. Here, the authors show upregulated ELC-phosphorylation in systolic heart failure and identify NIMArelated kinase 9 to bind to ELC mediating its calcium-dependent phosphorylation.
- Marion Müller
- , Rose Eghbalian
- & Benjamin Meder
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Article
| Open AccessTmem65 is critical for the structure and function of the intercalated discs in mouse hearts
The intercalated disc (ICD) is a membrane structure of the cardiac muscle involved in normal heart function. Here the authors report that knockdown of the ICD-bound transmembrane protein 65 results in impaired ICD structure, abnormal cardiac electrophysiology and cardiomyopathy in mice.
- Allen C. T. Teng
- , Liyang Gu
- & Anthony O. Gramolini
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Article
| Open AccessWhole genome sequence analysis of blood lipid levels in >66,000 individuals
Although the common genetic variants contributing to blood lipid levels have been studied, the contribution of rare variants is less understood. Here, the authors perform a rare coding and noncoding variant association study of blood lipid levels using whole genome sequencing data.
- Margaret Sunitha Selvaraj
- , Xihao Li
- & Pradeep Natarajan
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| Open AccessAllele-specific differential regulation of monoallelically expressed autosomal genes in the cardiac lineage
The authors use allele-specific single cell transcriptomic analysis to elucidate the establishment of monoallelic gene expression in the cardiac lineage. The findings emphasize the importance of allele-specific insight into gene regulation in development, homeostasis and disease.
- Gayan I. Balasooriya
- & David L. Spector
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Article
| Open AccessIntrinsic myocardial defects underlie an Rbfox-deficient zebrafish model of hypoplastic left heart syndrome
The developmental mechanisms responsible for the structural defects observed in hypoplastic left heart syndrome remain controversial. Using rbfox-deficient zebrafish, the authors implicate impaired cardiac function as a primary driver of disease.
- Mengmeng Huang
- , Alexander A. Akerberg
- & Caroline E. Burns
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Article
| Open AccessSingle-cell transcriptomics reveal cellular diversity of aortic valve and the immunomodulation by PPARγ during hyperlipidemia
Identifying the mechanisms underlying the early inflammatory phase of aortic valve disease is crucial for disease prevention. Here the authors perform single-cell RNA sequencing to show the immunomodulatory role of PPARγ in valvular endothelial cells during hyperlipidemia.
- Seung Hyun Lee
- , Nayoung Kim
- & Jae-Hoon Choi
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Article
| Open AccessThe complement C3-complement factor D-C3a receptor signalling axis regulates cardiac remodelling in right ventricular failure
Right ventricular (RV) failure is clinically crucial, but there is no specific therapy. Here, the authors show that the complement alternative pathway is activated in RV failure and that blockade of the pathway ameliorates RV failure in mice.
- Shogo Ito
- , Hisayuki Hashimoto
- & Shinsuke Yuasa
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Article
| Open AccessMild dyslipidemia accelerates tumorigenesis through expansion of Ly6Chi monocytes and differentiation to pro-angiogenic myeloid cells
Obesity and inflammation have been associated to cancer progression. Here, the authors show that high fat and cholesterol diet, in a non-obese context, promotes tumourigenesis through increasing inflammatory monocytes and myeloid-derived pro-angiogenic factors.
- Thi Tran
- , Jean-Remi Lavillegrand
- & Stephane Potteaux
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Article
| Open AccessClonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease
Clonal hematopoiesis, often caused by mutations in DNMT3A and TET2, is associated with blood cancer and coronary artery disease. Here, the authors conduct an epigenome-wide association study, finding that clonal hematopoiesis caused by DNMT3A vs. TET2 mutations has directionally opposing changes in DNA methylation profiles, with both promoting stem cell self-renewal.
- M d Mesbah Uddin
- , Ngoc Quynh H. Nguyen
- & Karen N. Conneely
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Article
| Open AccessBeiging of perivascular adipose tissue regulates its inflammation and vascular remodeling
Perivascular adipose tissue (PVAT) has been reported to undergo inflammatory changes in response to vascular injury. Here, the authors show that vascular injury induces the beiging (brown adipose tissue-like phenotype change) of PVAT, which fine-tunes inflammatory response as a protective mechanism.
- Yusuke Adachi
- , Kazutaka Ueda
- & Issei Komuro
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| Open AccessIdentification of risk loci for primary aldosteronism in genome-wide association studies
Detection of primary aldosteronism, the most common form of secondary arterial hypertension, is essential for targeted management and prevention of cardiovascular complications. Here, the authors identify genetic loci associated with primary aldosteronism, suggesting new mechanisms of disease.
- Edith Le Floch
- , Teresa Cosentino
- & Maria-Christina Zennaro
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Article
| Open AccessAMPK deficiency in smooth muscles causes persistent pulmonary hypertension of the new-born and premature death
AMPK modulates idiopathic and hypoxic pulmonary hypertension in adults, largely via unknown mechanisms. Here, the authors show that AMPK deficiency in smooth muscles causes persistent pulmonary hypertension of the new born and premature death in mice, due to increased muscularisation and remodeling of pulmonary arteries, reduced alveolar numbers and alveolar membrane thickening
- Javier Moral-Sanz
- , Sophronia A. Lewis
- & A. Mark Evans
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Article
| Open AccessWhole Genome Association Study of the Plasma Metabolome Identifies Metabolites Linked to Cardiometabolic Disease in Black Individuals
Most studies of the genetics of the metabolome have been done in individuals of European descent. Here, the authors integrate genomics and metabolomics in Black individuals, highlighting the value of whole genome sequencing in diverse populations and linking circulating metabolites to human disease.
- Usman A. Tahir
- , Daniel H. Katz
- & Robert E. Gerszten
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| Open AccessSpatiotemporal dynamics of macrophage heterogeneity and a potential function of Trem2hi macrophages in infarcted hearts
Cellular composition and function are not clearly defined in heart failure after myocardial infarction. Here, using single cell and spatial transcriptomics in a MI-HF mouse model, the authors show that macrophages expressing Trem2 are found within the infarcts and this could be a useful biomarker.
- Seung-Hyun Jung
- , Byung-Hee Hwang
- & Yeun-Jun Chung
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Article
| Open AccessGenome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities
Aortic distensibility is a risk factor for multiple cardiovascular events, but the genetic etiology is not well understood. Here, the authors identify genetic variants linked to aortic distensibility, highlighting mechanistic pathways and causal relationships between distensibility and both aortic aneurysms and brain small vessel disease.
- Catherine M. Francis
- , Matthias E. Futschik
- & Paul M. Matthews
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Article
| Open AccessCDC-like kinase 4 deficiency contributes to pathological cardiac hypertrophy by modulating NEXN phosphorylation
Phosphorylation catalyzed by kinases is a key event in signaling pathways involved in cardiomyocyte hypertrophy. Here the authors show that the kinase CLK4 ameliorates cardiac hypertrophy by phosphorylating NEXN.
- Jian Huang
- , Luxin Wang
- & Yi-Han Chen
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Article
| Open AccessNeprilysins regulate muscle contraction and heart function via cleavage of SERCA-inhibitory micropeptides
Muscle contraction depends on strictly controlled calcium transients within myocytes. Here, the authors show that the endopeptidase Neprilysin 4 represents an essential regulator of these transients and, consequently, of proper heart function.
- Ronja Schiemann
- , Annika Buhr
- & Heiko Meyer
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Article
| Open AccessTargeting transcription in heart failure via CDK7/12/13 inhibition
In this study, Hsu et al. show that inhibition of CDK7/12/13 attenuates maladaptive transcriptional activation in cultured cardiomyocytes and a mouse model of heart failure, suggesting that targeting the transcription machinery might be a therapeutic approach to treat heart failure with reduced ejection fraction.
- Austin Hsu
- , Qiming Duan
- & Saptarsi M. Haldar
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Article
| Open AccessThe RalGAPα1–RalA signal module protects cardiac function through regulating calcium homeostasis
Here the authors show that a RalGAPα1-RalA signal nexus regulates calcium homeostasis in cardiomyocytes via the calcium pump SERCA2a, which plays a protective role to maintain cardiac function under pressure overload conditions.
- Sangsang Zhu
- , Chao Quan
- & Shuai Chen
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Article
| Open AccessSingle-cell transcriptome atlas of the human corpus cavernosum
The corpus cavernosum is the most important structure for penile erection, and its dysfunction causes physiological and psychological problems. Here the authors perform single-cell RNA-sequencing on corpus cavernosum samples from males with normal erection and erectile dysfunction patients, providing insights into this pathology.
- LiangYu Zhao
- , Sha Han
- & Zheng Li
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Article
| Open AccessTargeting loop3 of sclerostin preserves its cardiovascular protective action and promotes bone formation
Antibodies targeting sclerostin can ameliorate postmenopausal osteoporosis but present some cardiovascular risk. Here the authors show that the cardiovascular and skeletal effects of sclerostin are mediated by different loops, suggesting ways to preserve the positive effects on bone formation while avoiding the negative cardiovascular consequences.
- Yuanyuan Yu
- , Luyao Wang
- & Ge Zhang
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Article
| Open AccessNeuropilin 1 and its inhibitory ligand mini-tryptophanyl-tRNA synthetase inversely regulate VE-cadherin turnover and vascular permeability
Functional vascular tree formation is a key step in many contexts, such as cancer, and Neuropilin1 (NRP1) has been associated with adhesion receptor endocytic turnover. Here, authors show NRP1 and its mini-WARS ligand play a role in reducing endothelial permeability.
- Noemi Gioelli
- , Lisa J. Neilson
- & Guido Serini
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Article
| Open AccessA SOX17-PDGFB signaling axis regulates aortic root development
Little is known about the developmental causes of aortic root defects. Here the authors show that the inactivation of Sox17 in aortic root endothelium results in aortic root defects affecting aortic valve and coronary ostium.
- Pengfei Lu
- , Ping Wang
- & Bin Zhou
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Article
| Open AccessCardiac disruption of SDHAF4-mediated mitochondrial complex II assembly promotes dilated cardiomyopathy
Functional succinate dehydrogenase (SDH) complex is vital to mitochondrial homeostasis. Here the authors show that disruption of SDH assembly in the heart causes dilated cardiomyopathy via impairing the mitochondrial integrity and metabolism and that mitochondrial interventions can be an effective approach to ameliorate the disease progression.
- Xueqiang Wang
- , Xing Zhang
- & Zhihui Feng
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Article
| Open AccessSex differences in heart mitochondria regulate diastolic dysfunction
In this paper, the authors show that sex differences in mitochondrial DNA levels and function in the heart contribute to sex biases in functions relevant to heart failure, identifying Acsl6 as a mitochondrial sex-biased regulator of diastolic function.
- Yang Cao
- , Laurent Vergnes
- & Aldons J. Lusis
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Article
| Open AccessT cell cholesterol efflux suppresses apoptosis and senescence and increases atherosclerosis in middle aged mice
Cholesterol efflux is mediated by specific transporters in T cells. Here the authors show that when the ABCA1/ABCG1 cholesterol transporters are absent, peripheral T cell numbers are reduced but activation increased with a premature aging phenotype of T cell senescence and apoptosis in middle aged Ldlr−/− mice.
- Venetia Bazioti
- , Anouk M. La Rose
- & Marit Westerterp
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Article
| Open AccessPerirenal adipose afferent nerves sustain pathological high blood pressure in rats
The sympathetic nervous system can contribute to the development of hypertension, but the neurogenic mechanisms involved are incompletely understood. Here the authors report that afferent nerves in the perirenal adipose tissue (PRAT) contribute to the maintenance of high blood pressure, and PRAT ablation, denervation or upregulation of calcitonin gene-related peptide reduce blood pressure in hypertensive rats.
- Peng Li
- , Boxun Liu
- & Xiangqing Kong
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Article
| Open AccessMapping the cardiac vascular niche in heart failure
The cardiac vascular niche is of major importance in homeostasis and disease, but knowledge of its complexity in response to injury remains limited. Here we combine lineage tracing with single cell RNA sequencing to show alterations in fibroblasts, endothelial and mural cells in hypertrophic remodeling.
- Fabian Peisker
- , Maurice Halder
- & Rafael Kramann
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Article
| Open AccessOmega-3 fatty acid epoxides produced by PAF-AH2 in mast cells regulate pulmonary vascular remodeling
Pulmonary hypertension is a fatal disease that causes right heart failure due to pulmonary artery stenosis. Here, the authors find that ω-3 epoxides produced by the phospholipase PAF-AH2 in mast cells regulate pulmonary vascular remodeling.
- Hidenori Moriyama
- , Jin Endo
- & Motoaki Sano
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Article
| Open AccessMolecular basis for gating of cardiac ryanodine receptor explains the mechanisms for gain- and loss-of function mutations
Ryanodine receptor 2 (RyR2) is a Ca2+ release channel essential for cardiac excitation-contraction coupling. Here, the authors use structural and functional analysis to reveal RyR2 gating mechanism and its alterations by pathogenic mutations.
- Takuya Kobayashi
- , Akihisa Tsutsumi
- & Haruo Ogawa
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Article
| Open AccessMitochondrial calcium uniporter stabilization preserves energetic homeostasis during Complex I impairment
Mitochondrial complex I deficiency is frequent in congenital, neurologic and cardiovascular disease. Here the authors demonstrate that Complex I stimulates the turnover of a mitochondrial calcium channel, which becomes stabilized during Complex I deficiency, preserving energetic homeostasis.
- Enrique Balderas
- , David R. Eberhardt
- & Dipayan Chaudhuri