Pubblicazioni recenti - cardiac fibroblast
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Distinct mononuclear diploid cardiac subpopulation with minimal cell-cell communications persists in embryonic and adult mammalian heart.
Front Med2023 Jun;():. doi: 10.1007/s11684-023-0987-9.
Zhu Miaomiao, Liang Huamin, Zhang Zhe, Jiang Hao, Pu Jingwen, Hang Xiaoyi, Zhou Qian, Xiang Jiacheng, He Ximiao,
Abstract
A small proportion of mononuclear diploid cardiomyocytes (MNDCMs), with regeneration potential, could persist in adult mammalian heart. However, the heterogeneity of MNDCMs and changes during development remains to be illuminated. To this end, 12 645 cardiac cells were generated from embryonic day 17.5 and postnatal days 2 and 8 mice by single-cell RNA sequencing. Three cardiac developmental paths were identified: two switching to cardiomyocytes (CM) maturation with close CM-fibroblast (FB) communications and one maintaining MNDCM status with least CM-FB communications. Proliferative MNDCMs having interactions with macrophages and non-proliferative MNDCMs (non-pMNDCMs) with minimal cell-cell communications were identified in the third path. The non-pMNDCMs possessed distinct properties: the lowest mitochondrial metabolisms, the highest glycolysis, and high expression of Myl4 and Tnni1. Single-nucleus RNA sequencing and immunohistochemical staining further proved that the Myl4Tnni1 MNDCMs persisted in embryonic and adult hearts. These MNDCMs were mapped to the heart by integrating the spatial and single-cell transcriptomic data. In conclusion, a novel non-pMNDCM subpopulation with minimal cell-cell communications was unveiled, highlighting the importance of microenvironment contribution to CM fate during maturation. These findings could improve the understanding of MNDCM heterogeneity and cardiac development, thus providing new clues for approaches to effective cardiac regeneration.
© 2023. Higher Education Press.
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Association of serum 25-hydroxyvitamin D3, fibroblast growth factor-23, and C1q/tumor necrosis factor-related protein-3 with coronary artery calcification in nondialysis chronic kidney disease patients.
Ren Fail2023 Dec;45(1):2220412. doi: 10.1080/0886022X.2023.2220412.
Zhu Yuanjie, Hu Zhijuan, Liu Yu, Qin Congcong, Chen Xing, Shi Yanan, Wang Lijun,
Abstract
OBJECTIVE:
To assess serum 25-hydroxyvitamin D3 (25(OH)D3), fibroblast growth factor 23 (FGF23), and C1q/tumor necrosis factor-related protein-3 (CTRP3) levels in nondialysis chronic kidney disease (CKD) patients and their relationship with coronary artery calcification (CAC).
METHODS:
One hundred and twenty-eight patients diagnosed with CKD were selected and all underwent cardiac computed tomography. CAC was assessed using the Agatston score, and coronary artery calcification score (CACs) >10 was identified as CAC. The differences in serum 25(OH)D3, FGF23, and CTRP3 levels between the CAC and non-CAC groups were analyzed. Their correlation with CACs was assessed by Spearman's analysis, and logistic regression analysis was used to find risk factors for CAC.
RESULTS:
Compared to the non-CAC group, the CAC group was older (64.21 ± 9.68 years), with a higher percentage of hypertension (93.10%) and diabetes (63.80%) and higher levels of serum CTRP3 [1079.20 (644.4-1567.2) ng/mL]. However, there was no significant difference in serum 25(OH)D3 and FGF23 between these two groups. The high level CTRP3 group had a higher prevalence of CAC (61.5%). Logistic regression results showed that age, diabetes, decreased 25(OH)D3 (odds ratio (OR) = 0.95, = .030) and high levels of CTRP3 (OR = 3.19, = .022) were risk factors for CAC in nondialysis CKD patients.
CONCLUSIONS:
Serum CTRP3 levels progressively increased with the progression of kidney disease, while 25(OH)D3 levels progressively decreased. Decreased 25(OH)D3 and high levels of CTRP3 are associated with CAC in patients with nondialysis CKD.
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Fibroblast-specific inflammasome activation predisposes to atrial fibrillation.
bioRxiv2023 May;():. doi: 2023.05.18.541326.
Li Luge, Coarfa Cristian, Yuan Yue, Abu-Taha Issam, Wang Xiaolei, Song Jia, Koirala Amrit, Grimm Sandra L, Kamler Markus, Mullany Lisa K, Tallquist Michelle, Nattel Stanley, Dobrev Dobromir, Li Na,
Abstract
BACKGROUND:
Recent work has shown that the NLR-family-pyrin-domain-containing 3 (NLRP3) inflammasome is expressed in cardiomyocytes and when specifically activated causes atrial electrical remodeling and arrhythmogenicity. Whether the NLRP3-inflammasome system is functionally important in cardiac fibroblasts (FBs) remains controversial. In this study, we sought to uncover the potential contribution of FB NLRP3-inflammasome signaling to the control of cardiac function and arrhythmogenesis.
METHODS:
Digital-PCR was performed to determine the expression of NLRP3-pathway components in FBs isolated from human biopsy samples of AF and sinus rhythm patients. NLRP3-system protein expression was determined by immunoblotting in atria of canines with electrically maintained AF. Using the inducible, resident fibroblast (FB)-specific Tcf21-promoter-Cre system (Tcf21iCre as control), we established a FB-specific knockin (FB-KI) mouse model with FB-restricted expression of constitutively active NLRP3. Cardiac function and arrhythmia susceptibility in mice were assessed by echocardiography, programmed electrical stimulation, and optical mapping studies.
RESULTS:
NLRP3 and IL1B were upregulated in atrial FBs of patients with persistent AF. Protein levels of NLRP3, ASC, and pro-Interleukin-1? were increased in atrial FBs of a canine AF model. Compared with the control mice, FB-KI mice exhibited enlarged left atria (LA) and reduced LA contractility, a common determinant of AF. The FBs from FB-KI mice were more transdifferentiated, migratory, and proliferative compared to the FBs from control mice. FB-KI mice showed increased cardiac fibrosis, atrial gap junction remodeling, and reduced conduction velocity, along with increased AF susceptibility. These phenotypic changes were supported by single nuclei (sn)RNA-seq analysis, which revealed enhanced extracellular matrix remodeling, impaired communication among cardiomyocytes, and altered metabolic pathways across multiple cell types.
CONCLUSIONS:
Our results show that the FB-restricted activation of the NLRP3-inflammasome system leads to fibrosis, atrial cardiomyopathy, and AF. Activation of NLRP3-inflammasome in resident FBs exhibits cell-autonomous function by increasing the activity of cardiac FBs, fibrosis, and connexin remodeling. This study establishes the NLRP3-inflammasome as a novel FB-signaling pathway contributing to AF pathogenesis.
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Elevated interleukin-11 in systemic sclerosis and role in disease pathogenesis.
J Dermatol2023 Jun;():. doi: 10.1111/1346-8138.16854.
Steadman Thomas, O'Reilly Steven,
Abstract
Systemic sclerosis (SSc) is an autoimmune connective tissue disease in which there is elevated inflammation, aberrant cytokine expression, and subsequent fibrosis. Interleukin-11 (IL-11) is a recently described profibrotic cytokine that can mediate fibrosis in the heart, lungs, and skin and is upregulated by transforming Growth Factor-? (TGF-?1). The objective of this study was to quantify the serum levels of IL-11 in early diffuse SSc patients. Also, if IL-11 could regulate the alarmin IL-33 in dermal fibroblasts was quantified. Early diffuse SSc patient sera was isolated and IL-11 was quantified by specific commercial ELISA compared to healthy control (n?=?17). Healthy dermal fibroblasts were cultured in vitro and then serum starved and incubated with or without recombinant IL-11. At specific early and late time points the supernatant was quantified for the alarmin IL-33 by specific ELISA. In early diffuse SSc patients it was demonstrated that they have elevated IL-11 in their sera. In a subgroup of SSc patients with interstitial lung disease (ILD) this elevation was particularly pronounced compared to those devoid of fibrotic lung disease. In vitro incubation of healthy dermal fibroblasts led to a significant induction of IL-33 cytokine release into the cell media. IL-11 is a profibrotic cytokine that is elevated in early diffuse SSc and is particularly elevated in those with ILD. This suggests that IL-11 could be a possible biomarker of ILD in SSc. It was also found that IL-11 led to release of the cytokine alarmin IL-33 in fibroblasts at earlier time points but not late time points, suggesting early stimulation elicits an inflammatory response in the local microenvironment but prolonged stimulation leads to fibrosis.
© 2023 Japanese Dermatological Association.
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Molecular Imaging of Myocardial Fibroblast Activation in Patients with Advanced Aortic Stenosis Before Transcatheter Aortic Valve Replacement: A Pilot Study.
J Nucl Med2023 Jun;():. doi: jnumed.122.265147.
Diekmann Johanna, Neuser Jonas, Röhrich Manuel, Derlin Thorsten, Zwadlo Carolin, Koenig Tobias, Weiberg Desiree, Jäckle Felix, Kempf Tibor, Ross Tobias L, Tillmanns Jochen, Thackeray James T, Widder Julian, Haberkorn Uwe, Bauersachs Johann, Bengel Frank M,
Abstract
Using multimodal imaging, we investigated the extent and functional correlates of myocardial fibroblast activation in patients with aortic stenosis (AS) scheduled for transcatheter aortic valve replacement (TAVR). AS may cause myocardial fibrosis, which is associated with disease progression and may limit response to TAVR. Novel radiopharmaceuticals identify upregulation of fibroblast activation protein (FAP) as a cellular substrate of cardiac profibrotic activity. Twenty-three AS patients underwent Ga-FAP inhibitor 46 (Ga-FAPI) PET, cardiac MRI, and echocardiography within 1-3 d before TAVR. Imaging parameters were correlated and then were integrated with clinical and blood biomarkers. Control cohorts of subjects without a history of cardiac disease and with ( = 5) and without ( = 9) arterial hypertension were compared with matched AS subgroups. Myocardial FAP volume varied significantly among AS subjects (range, 1.54-138 cm, mean ± SD, 42.2?±?35.6 cm) and was significantly higher than in controls with (7.42?±?8.56 cm, = 0.007) and without (2.90?±?6.67 cm;
© 2023 by the Society of Nuclear Medicine and Molecular Imaging.
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Review: Acetylation Mechanisms andTargeted Therapies in Cardiac Fibrosis.
Pharmacol Res2023 Jun;():106815. doi: 10.1016/j.phrs.2023.106815.
Liu Weikang, Yuan Qiuhuan, Cao Shengchuan, Wang Guoying, Liu Xiangguo, Xia Yanan, Bian Yuan, Xu Feng, Chen Yuguo,
Abstract
Cardiac fibrosis is a common pathophysiological remodeling process that occurs in a variety of cardiovascular diseases and greatly influences heart structure and function, progressively leading to the development of heart failure. However, to date, few effective therapies for cardiac fibrosis exist. Abnormal proliferation, differentiation, and migration of cardiac fibroblasts are responsible for the excessive deposition of extracellular matrix in the myocardium. Acetylation, a widespread and reversible protein post-translational modification, plays an important role in the development of cardiac fibrosis by adding acetyl groups to lysine residues. Many acetyltransferases and deacetylases regulate the dynamic alterations of acetylation in cardiac fibrosis, regulating a range of pathogenic conditions including oxidative stress, mitochondrial dysfunction, and energy metabolism disturbance. In this review, we demonstrate the critical roles that acetylation modifications caused by different types of pathological injury play in cardiac fibrosis. Furthermore, we propose therapeutic acetylation-targeting strategies for the prevention and treatment of patients with cardiac fibrosis.
Copyright © 2023. Published by Elsevier Ltd.
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Biomimetic Electrospun Scaffold-Based In Vitro Model Resembling the Hallmarks of Human Myocardial Fibrotic Tissue.
ACS Biomater Sci Eng2023 Jun;():. doi: 10.1021/acsbiomaterials.3c00483.
Ruocco Gerardina, Zoso Alice, Mortati Leonardo, Carmagnola Irene, Chiono Valeria,
Abstract
Adverse remodeling post-myocardial infarction is hallmarked by the phenotypic change of cardiac fibroblasts (CFs) into myofibroblasts (MyoFs) and over-deposition of the fibrotic extracellular matrix (ECM) mainly composed by fibronectin and collagens, with the loss of tissue anisotropy and tissue stiffening. Reversing cardiac fibrosis represents a key challenge in cardiac regenerative medicine. Reliable models of human cardiac fibrotic tissue could be useful for preclinical testing of new advanced therapies, addressing the limited predictivity of traditional 2D cell cultures and animal models. In this work, we engineered a biomimetic model, reproducing the morphological, mechanical, and chemical cues of native cardiac fibrotic tissue. Polycaprolactone (PCL)-based scaffolds with randomly oriented fibers were fabricated by solution electrospinning technique, showing homogeneous nanofibers with an average size of 131 ± 39 nm. PCL scaffolds were then surface-functionalized with human type I collagen (C1) and fibronectin (F) by dihydroxyphenylalanine (DOPA)-mediated mussel-inspired approach (PCL/polyDOPA/C1F), in order to mimic fibrotic cardiac tissue-like ECM composition and support human CF culture. BCA assay confirmed the successful deposition of the biomimetic coating and its stability during 5 days of incubation in phosphate-buffered saline. Immunostaining for C1 and F demonstrated their homogeneous distribution in the coating. AFM mechanical characterization showed that PCL/polyDOPA/C1F scaffolds, in wet conditions, resembled fibrotic tissue stiffness with an average Young's modulus of about 50 kPa. PCL/polyDOPA/C1F membranes supported human CF (HCF) adhesion and proliferation. Immunostaining for ?-SMA and quantification of ?-SMA-positive cells showed HCF activation into MyoFs in the absence of a transforming growth factor ? (TGF-?) profibrotic stimulus, suggesting the intrinsic ability of biomimetic PCL/polyDOPA/C1F scaffolds to sustain the development of cardiac fibrotic tissue. A proof-of-concept study making use of a commercially available antifibrotic drug confirmed the potentialities of the developed model for drug efficacy testing. In conclusion, the proposed model was able to replicate the main hallmarks of early-stage cardiac fibrosis, appearing as a promising tool for future preclinical testing of advanced regenerative therapies.
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Silencing of UTX Mitigates Aging-Associated Cardiac Fibrosis via Blocking Cardiac Fibroblasts-to-Myofibroblasts Trans-Differentiation.
Anatol J Cardiol2023 Jun;():. doi: 10.14744/AnatolJCardiol.2023.2777.
Li Chao, Lin Tiantian, Li Delin, Si Daoyuan, Sun Huan, Yang Sibao, Zhang Zhongfan, Zhang Qian, Shi Kaiyao,
Abstract
BACKGROUND:
Cardiac fibrosis increases with age. Fibroblast activation plays an essential role in cardiac fibrosis. Histone modifications are involved in various chromatin-dependent processes. Attenuation of the histone H3 trimethylation on lysine 27 demethylase UTX by RNA interference or heterozygous mutation extends lifespan in worm. The objective of this study was to explore whether epigenetic silencing of UTX mitigates aging-associated cardiac fibrosis.
METHODS:
Middle-aged mice (15 months old) were used and started to receive adeno-associated virus-scrambled-small hairpin RNA and adeno-associated virus-UTX-small hairpin RNA every 3 months from 15 months to 21 months, respectively. The mice were euthanized at 24 months of age (length of the study).
RESULTS:
Adeno-associated virus-UTX-small hairpin RNA delivery significantly attenu-ated aging-associated increase in blood pressure, especially in diastolic blood pressure, indicating silencing of UTX rescued aging-associated cardiac dysfunction. Aging-associated cardiac fibrosis is characterized by fibroblast activation and abundant extracellular matrix deposition, including collagen deposition and alpha smooth muscle actin activation. Silencing of UTX abolished collagen deposition and alpha smooth muscle actin activation, decreased serum transforming growth factor ?, blocked cardiac fibro blast s-to- myofi brobl asts trans-differentiation by elevation of cardiac resident mature fibroblast markers, TCF21, and platelet-derived growth factor receptor alpha, which are important proteins for maintaining cardiac fibroblast physiological function. In the mechanistic study, adeno-associated virus-UTX-small hairpin RNA blocked transforming growth factor ?-induced cardiac fibro blast s-to- myofi brobl asts trans-differentiation in isolated fibroblasts from 24-month-old mouse heart. The same results demonstrated as the in vivo study.
CONCLUSIONS:
Silencing of UTX attenuates aging-associated cardiac fibrosis via blocking cardiac fibroblasts-to-myofibroblasts transdifferentiation and consequently attenuates aging-associated cardiac dysfunction and cardiac fibrosis.
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Nanoengineering of gold nanoribbon-embedded isogenic stem cell-derived cardiac organoids.
RSC Adv2023 Jun;13(25):16985-17000. doi: 10.1039/d3ra01811c.
Patino-Guerrero Alejandra, Esmaeili Hamid, Migrino Raymond Q, Nikkhah Mehdi,
Abstract
Cardiac tissue engineering is an emerging field providing tools to treat and study cardiovascular diseases (CVDs). In the past years, the integration of stem cell technologies with micro- and nanoengineering techniques has enabled the creation of novel engineered cardiac tissues (ECTs) with potential applications in disease modeling, drug screening, and regenerative medicine. However, a major unaddressed limitation of stem cell-derived ECTs is their immature state, resembling a neonatal phenotype and genotype. The modulation of the cellular microenvironment within the ECTs has been proposed as an efficient mechanism to promote cellular maturation and improve features such as cellular coupling and synchronization. The integration of biological and nanoscale cues in the ECTs could serve as a tool for the modification and control of the engineered tissue microenvironment. Here we present a proof-of-concept study for the integration of biofunctionalized gold nanoribbons (AuNRs) with hiPSC-derived isogenic cardiac organoids to enhance tissue function and maturation. We first present extensive characterization of the synthesized AuNRs, their PEGylation and cytotoxicity evaluation. We then evaluated the functional contractility and transcriptomic profile of cardiac organoids fabricated with hiPSC-derived cardiomyocytes (mono-culture) as well as with hiPSC-derived cardiomyocytes and cardiac fibroblasts (co-culture). We demonstrated that PEGylated AuNRs are biocompatible and do not induce cell death in hiPSC-derived cardiac cells and organoids. We also found an improved transcriptomic profile of the co-cultured organoids indicating maturation of the hiPSC-derived cardiomyocytes in the presence of cardiac fibroblasts. Overall, we present for the first time the integration of AuNRs into cardiac organoids, showing promising results for improved tissue function.
This journal is © The Royal Society of Chemistry.
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Transcriptome data analysis of primary cardiomyopathies reveals perturbations in arachidonic acid metabolism.
Front Cardiovasc Med2023 ;10():1110119. doi: 1110119.
Chauhan Pankaj Kumar, Sowdhamini Ramanathan,
Abstract
INTRODUCTION:
Cardiomyopathies are complex heart diseases with significant prevalence around the world. Among these, primary forms are the major contributors to heart failure and sudden cardiac death. As a high-energy demanding engine, the heart utilizes fatty acids, glucose, amino acid, lactate and ketone bodies for energy to meet its requirement. However, continuous myocardial stress and cardiomyopathies drive towards metabolic impairment that advances heart failure (HF) pathogenesis. So far, metabolic profile correlation across different cardiomyopathies remains poorly understood.
METHODS:
In this study, we systematically explore metabolic differences amongst primary cardiomyopathies. By assessing the metabolic gene expression of all primary cardiomyopathies, we highlight the significantly shared and distinct metabolic pathways that may represent specialized adaptations to unique cellular demands. We utilized publicly available RNA-seq datasets to profile global changes in the above diseases (|| ? 0.28 and BH 0.1) and performed gene set analysis (GSA) using the PAGE statistics on KEGG pathways.
RESULTS:
Our analysis demonstrates that genes in arachidonic acid metabolism (AA) are significantly perturbed across cardiomyopathies. In particular, the arachidonic acid metabolism gene interacts with fibroblast marker genes and can potentially influence fibrosis during cardiomyopathy.
CONCLUSION:
The profound significance of AA metabolism within the cardiovascular system renders it a key player in modulating the phenotypes of cardiomyopathies.
© 2023 Chauhan and Sowdhamini.
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Cardiac Fibroblast Activation Induced by Oxygen-Glucose Deprivation Depends on the HIF-1?/miR-212-5p/KLF4 Pathway.
J Cardiovasc Transl Res2023 Jun;():. doi: 10.1007/s12265-023-10360-2.
Li Hongbing, Li Chenxing, Zheng Tao, Wang Yaning, Wang Jin, Fan Xiaojuan, Zheng Xueyang, Tian Gang, Yuan Zuyi, Chen Tao,
Abstract
It is widely accepted that miRNAs play an important role in the pathogenesis of myocardial fibrosis. This study aimed to identify a new pathway of miR-212-5p in the activation of human cardiac fibroblasts (HCFs) induced by oxygen-glucose deprivation (OGD). First, we found that KLF4 protein was markedly decreased in OGD-induced HCFs. Then, bioinformatics analysis and verification experiments were used to identify the existence of an interaction of KLF4 with miR-212-5p. Functional experiments indicated that OGD significantly upregulated the expression of hypoxia inducible factor-1 alpha (HIF-1?) in HCFs, which positively regulated miR-212-5p transcription by binding to its promoter. MiR-212-5p inhibited the expression of Krüppel-like factor 4 (KLF4) protein by binding to the 3' untranslated coding regions (UTRs) of KLF4 mRNA. Inhibition of miR-212-5p effectively inhibited the activation of OGD-induced HCFs by upregulating KLF4 expression and inhibited cardiac fibrosis in vivo and in vitro.
© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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Atrial epicardial adipose tissue abundantly secretes myeloperoxidase and activates atrial fibroblasts in patients with atrial fibrillation.
J Transl Med2023 Jun;21(1):366. doi: 366.
Meulendijks Eva R, Al-Shama Rushd F M, Kawasaki Makiri, Fabrizi Benedetta, Neefs Jolien, Wesselink Robin, Ernault Auriane C, Piersma Sander, Pham Thang V, Jimenez Connie R, Knol Jaco C, van Boven Wim J P, Driessen Antoine H G, de Vries Tim A C, van der Leeden Britt, Niessen Hans W M, de Boer Onno J, Krul Sébastien P J, de Groot Joris R,
Abstract
BACKGROUND:
Epicardial adipose tissue (EAT) secretome induces fibrosis. Fibrosis, primarily extracellular matrix (ECM) produced by fibroblasts, creates a substrate for atrial fibrillation (AF). Whether the EAT secretome from patients with AF activates human atrial fibroblasts and through which components, remains unexplored.
RESEARCH AIMS:
(a) To investigate if the EAT secretome from patients with versus without AF increases ECM production in atrial fibroblasts. (b) To identify profibrotic proteins and processes in the EAT secretome and EAT from patients with, who will develop (future onset), and without AF.
METHODS:
Atrial EAT was obtainded during thoracoscopic ablation (AF, n?=?20), or open-heart surgery (future onset and non-AF, n?=?35). ECM gene expression of human atrial fibroblasts exposed to the EAT secretome and the proteomes of EAT secretome and EAT were assessed in patients with and without AF. Myeloperoxidase and neutrophil extracellular traps (NETs) were assessed immunohistochemically in patients with paroxysmal, persistent, future onset, and those who remain free of AF (non-AF).
RESULTS:
The expression of COL1A1 and FN1 in fibroblasts exposed to secretome from patients with AF was 3.7 and 4.7 times higher than in patients without AF (p?0.05). Myeloperoxidase was the most increased protein in the EAT secretome and EAT from patients with versus without AF (FC 18.07 and 21.57, p?0.005), as was the gene-set neutrophil degranulation. Immunohistochemically, myeloperoxidase was highest in persistent (FC 13.3, p?0.0001) and increased in future onset AF (FC 2.4, p?=?0.02) versus non-AF. Myeloperoxidase aggregated subepicardially and around fibrofatty infiltrates. NETs were increased in patients with persistent versus non-AF (p?=?0.03).
CONCLUSION:
In AF, the EAT secretome induces ECM gene expression in atrial fibroblasts and contains abundant myeloperoxidase. EAT myeloperoxidase was increased prior to AF onset, and both myeloperoxidase and NETs were highest in persistent AF, highlighting the role of EAT neutrophils in the pathophysiology of AF.
© 2023. The Author(s).
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Single-cell RNA sequencing reveals a mechanism underlying the susceptibility of the left atrial appendage to intracardiac thrombogenesis during atrial fibrillation.
Clin Transl Med2023 Jun;13(6):e1297. doi: e1297.
Yang Jie, Tan Hu, Sun Mengjia, Chen Renzheng, Jian Zhao, Song Yuanbin, Zhang Jihang, Bian Shizhu, Zhang Bo, Zhang Yi, Gao Xubin, Chen Zhen, Wu Boji, Ye Xiaowei, Lv Hailin, Liu Zhen, Huang Lan,
Abstract
BACKGROUND:
Atrial fibrillation (AF) is associated with an increased risk of thrombosis of the left atrial appendage (LAA). However, the molecular mechanisms underlying this site-specificity remain poorly understood. Here, we present a comparative single-cell transcriptional profile of paired atrial appendages from patients with AF and illustrate the chamber-specific properties of the main cell types.
METHODS:
Single-cell RNA sequencing analysis of matched atrial appendage samples from three patients with persistent AF was evaluated by 10× genomics. The AF mice model was created using Tbx5 knockout mice. Validation experiments were performed by glutathione S-transferase pull-down assays, coimmunoprecipitation (Co-IP), cleavage assays and shear stress experiments in vitro.
RESULTS:
In LAA, phenotype switching from endothelial cells to fibroblasts and inflammation associated with proinflammatory macrophage infiltration were observed. Importantly, the coagulation cascade is highly enriched in LAA endocardial endothelial cells (EECs), accompanying the up-regulation of a disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1) and the down-regulation of the tissue factor pathway inhibitor (TFPI) and TFPI2. Similar alterations were verified in an AF mouse model (Tbx5 ) and EECs treated with simulated AF shear stress in vitro. Furthermore, we revealed that the cleavage of both TFPI and TFPI2 based on their interaction with ADAMTS1 would lead to loss of anticoagulant activities of EECs.
CONCLUSIONS:
This study highlights the decrease in the anticoagulant status of EECs in LAA as a potential mechanism underlying the propensity for thrombosis, which may aid the development of anticoagulation therapeutic approaches targeting functionally distinct cell subsets or molecules during AF.
© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
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Irisin attenuates angiotensin II-induced atrial fibrillation and atrial fibrosis via LOXL2 and TGF?1/Smad2/3 signaling pathways.
Iran J Basic Med Sci2023 ;26(6):717-724. doi: 10.22038/IJBMS.2023.68639.14967.
Wu Yingbiao, Luo Jun, Song Xiang, Gu Wei, Wang Saihua, Hao Shuwen, Dong Zhiwu, Ning Zhongping,
Abstract
OBJECTIVES:
Irisin was reported as a cardioprotective and anti-oxidative effector, while the effect on atrial fibrosis is unknown. The current research examined irisin's function in atrial fibrillation (AF); atrial fibrosis brought on by Ang II can be suppressed, thus lessening the risk of developing AF.
MATERIALS AND METHODS:
246 individuals were enrolled in the present case-control study. Chinese AF patients (n=126), 83 of whom were paroxysmal AF (PAF), 43 patients with persistent AF (PeAF), and 120 healthy controls. Saline or Ang II (2.0 mg/kg/day) was subcutaneously injected into healthy male C57BL/6 mice for four weeks. Once daily for four weeks, intraperitoneal injections of exogenous irisin (500 g/kg/day) were administered.
RESULTS:
In comparison to PAF patients and healthy controls (all P
CONCLUSION:
The study results speculated that irisin could be a potential AF target, and it inhibited atrial fibrosis and significantly impaired increased AF susceptibility through inactivation of LOXL2 and the TGF-?/Smad pathway.
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TRIM44 aggravates cardiac fibrosis after myocardial infarction via TAK1 stabilization.
Cell Signal2023 Jun;():110744. doi: 10.1016/j.cellsig.2023.110744.
Qian Hao, Lu Zhengri, Hao Chunshu, Zhao Yuanyuan, Bo Xiangwei, Hu Ya, Zhang Yao, Yao Yuyu, Ma Genshan, Chen Lijuan,
Abstract
Myocardial infarction (MI) is one of the most dangerous cardiovascular events. Cardiac fibrosis is a common pathological feature of remodeling after injury that is related to adverse clinical results with no effective treatment. Previous studies have confirmed that TRIM44, an E3 ligase, can promote the proliferation and migration of various tumor cells. However, the role of TRIM44 in cardiac fibrosis remains unknown. Models of TGF-?1 stimulation and MI-induced fibrosis were established to investigate the role and potential underlying mechanism of TRIM44 in cardiac fibrosis. The results showed that cardiac fibrosis was significantly inhibited after TRIM44 knockdown in a mouse model of MI, while it was enhanced when TRIM44 was overexpressed. Furthermore, in vitro studies showed that fibrosis markers were significantly reduced in cardiac fibroblasts (CFs) with TRIM44 knockdown, whereas TRIM44 overexpression promoted the expression of fibrosis markers. Mechanistically, TRIM44 maintains TAK1 stability by inhibiting the degradation of k48-linked polyubiquitination-mediated ubiquitination, thereby increasing phosphorylated TAK1 expression in the fibrotic environment and activating MAPKs to promote fibrosis. Pharmacological inhibition of TAK1 phosphorylation reversed the fibrogenic effects of TRIM44 overexpression. Combined, these results suggest that TRIM44 is a potential therapeutic target for cardiac fibrosis.
Copyright © 2023. Published by Elsevier Inc.
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An Efficient and Reproducible Method for the Isolation and Culture of Primary Cardiomyocytes from Adult Zebrafish.
Zebrafish2023 Jun;():. doi: 10.1089/zeb.2023.0015.
Zhang Chunyan, Sun Yanyi, Chen Zhenyue,
Abstract
Zebrafish is a popular animal model in regeneration studies due to their ability to regenerate the heart. Primary cardiomyocytes could be an alternative tool for studying the intrinsic mechanisms of cardiovascular disease . Thus, our objective is to develop an efficient protocol to isolate primary cardiomyocytes from zebrafish hearts. Low concentration of digestive enzyme (0.5?mg/mL collagenase type II) was utilized in our protocol to obtain single-cell suspension. The ventricles were fragmented, mechanically pipetted, and constantly shaken to ensure adequate contact between the tissues and the enzyme. Preplating the cell suspension onto culture plates for 2?h helped remove cardiac fibroblasts. The purity of isolated cells was validated by flow cytometry analysis of transgenic zebrafish with cardiomyocyte-specific expression of enhanced green fluorescent protein (EGFP) or endothelial cell-specific expression of mCherry. Quantitative real-time PCR analysis revealed a high level of the purity, with cardiac fibroblasts, endothelial cells, and epicardial cell markers scarcely detected in the purified cells. Altogether, this study established a reproducible protocol for isolating primary cardiomyocytes with high purity and activity from adult zebrafish hearts that can be cultured for up to 4 weeks. This protocol provides a valuable tool for studying the intrinsic mechanisms of cardiovascular disease using primary cardiomyocytes.
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IL-6 helps weave the inflammatory web during acute coronary syndromes.
J Clin Invest2023 Jun;133(11):. doi: e167670.
Nakao Tetsushi, Libby Peter,
Abstract
The cytokine IL-6 has well-known proinflammatory roles in aging and ischemic heart disease. In this issue of the JCI, Alter and colleagues used mouse experiments and human tissue to investigate the source of IL-6 following myocardial infarction. The authors showed that cardiac fibroblasts produced IL-6 after coronary ligation in mice and proposed the existence of a pathway involving adenosine signaling via the adenosine A2b receptor. The findings underscore the complexity of IL-6 biology in ischemic heart disease and identify an adenosine/IL-6 pathway that warrants consideration for targeting as a modulator of cardiovascular risk.
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Single-cell analysis of adult human heart across healthy and cardiovascular disease patients reveals the cellular landscape underlying SARS-CoV-2 invasion of myocardial tissue through ACE2.
J Transl Med2023 May;21(1):358. doi: 358.
Chen Cong, Wang Jie, Liu Yong-Mei, Hu Jun,
Abstract
BACKGROUND:
The distribution of ACE2 and accessory proteases (ANAD17 and CTSL) in cardiovascular tissue and the host cell receptor binding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are crucial to understanding the virus's cell invasion, which may play a significant role in determining the viral tropism and its clinical manifestations.
METHODS:
We conducted a comprehensive analysis of the cell type-specific expression of ACE2, ADAM17, and CTSL in myocardial tissue from 10 patients using RNA sequencing. Our study included a meta-analysis of 2 heart single-cell RNA-sequencing studies with a total of 90,024 cells from 250 heart samples of 10 individuals. We used co-expression analysis to locate specific cell types that SARS-CoV-2 may invade.
RESULTS:
Our results revealed cell-type specific associations between male gender and the expression levels of ACE2, ADAM17, and CTSL, including pericytes and fibroblasts. AGT, CALM3, PCSK5, NRP1, and LMAN were identified as potential accessory proteases that might facilitate viral invasion. Enrichment analysis highlighted the extracellular matrix interaction pathway, adherent plaque pathway, vascular smooth muscle contraction inflammatory response, and oxidative stress as potential immune pathways involved in viral infection, providing potential molecular targets for therapeutic intervention. We also found specific high expression of IFITM3 and AGT in pericytes and differences in the IFN-II signaling pathway and PAR signaling pathway in fibroblasts from different cardiovascular comorbidities.
CONCLUSIONS:
Our data indicated possible high-risk groups for COVID-19 and provided emerging avenues for future investigations of its pathogenesis.
TRIAL REGISTRATION:
(Not applicable).
© 2023. The Author(s).
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Human pluripotent stem cell-based models of heart development and disease.
Cells Dev2023 May;175():203857. doi: 10.1016/j.cdev.2023.203857.
Velichkova Gabriel, Dobreva Gergana,
Abstract
The heart is a complex organ composed of distinct cell types, such as cardiomyocytes, cardiac fibroblasts, endothelial cells, smooth muscle cells, neuronal cells and immune cells. All these cell types contribute to the structural, electrical and mechanical properties of the heart. Genetic manipulation and lineage tracing studies in mice have been instrumental in gaining critical insights into the networks regulating cardiac cell lineage specification, cell fate and plasticity. Such knowledge has been of fundamental importance for the development of efficient protocols for the directed differentiation of pluripotent stem cells (PSCs) in highly specialized cardiac cell types. In this review, we summarize the evolution and current advances in protocols for cardiac subtype specification, maturation, and assembly in cardiac microtissues and organoids.
Copyright © 2023 Elsevier B.V. All rights reserved.
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Indian Hedgehog release from TNF-activated renal epithelia drives local and remote organ fibrosis.
Sci Transl Med2023 May;15(698):eabn0736. doi: 10.1126/scitranslmed.abn0736.
O'Sullivan Eoin D, Mylonas Katie J, Xin Cuiyan, Baird David P, Carvalho Cyril, Docherty Marie-Helena, Campbell Ross, Matchett Kylie P, Waddell Scott H, Walker Alexander D, Gallagher Kevin M, Jia Siyang, Leung Steve, Laird Alexander, Wilflingseder Julia, Willi Michaela, Reck Maximilian, Finnie Sarah, Pisco Angela, Gordon-Keylock Sabrina, Medvinsky Alexander, Boulter Luke, Henderson Neil C, Kirschner Kristina, Chandra Tamir, Conway Bryan R, Hughes Jeremy, Denby Laura, Bonventre Joseph V, Ferenbach David A,
Abstract
Progressive fibrosis is a feature of aging and chronic tissue injury in multiple organs, including the kidney and heart. Glioma-associated oncogene 1 expressing (Gli1) cells are a major source of activated fibroblasts in multiple organs, but the links between injury, inflammation, and Gli1 cell expansion and tissue fibrosis remain incompletely understood. We demonstrated that leukocyte-derived tumor necrosis factor (TNF) promoted Gli1 cell proliferation and cardiorenal fibrosis through induction and release of Indian Hedgehog (IHH) from renal epithelial cells. Using single-cell-resolution transcriptomic analysis, we identified an "inflammatory" proximal tubular epithelial (iPT) population contributing to TNF- and nuclear factor ?B (NF-?B)-induced IHH production in vivo. TNF-induced Ubiquitin D () expression was observed in human proximal tubular cells in vitro and during murine and human renal disease and aging. Studies using pharmacological and conditional genetic ablation of TNF-induced IHH signaling revealed that IHH activated canonical Hedgehog signaling in Gli1 cells, which led to their activation, proliferation, and fibrosis within the injured and aging kidney and heart. These changes were inhibited in mice by deletion in -expressing cells or by pharmacological blockade of TNF, NF-?B, or Gli1 signaling. Increased amounts of circulating IHH were associated with loss of renal function and higher rates of cardiovascular disease in patients with chronic kidney disease. Thus, IHH connects leukocyte activation to Gli1 cell expansion and represents a potential target for therapies to inhibit inflammation-induced fibrosis.
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