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Pubblicazioni recenti - cardiac fibroblast
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Cardiac Fibrosis Is Associated With Decreased Circulating Levels of Full-Length CILP in Heart Failure.
JACC Basic Transl Sci2020 May;5(5):432-443. doi: 10.1016/j.jacbts.2020.01.016.
Park Shuin, Ranjbarvaziri Sara, Zhao Peng, Ardehali Reza,
Abstract
Cardiac fibrosis is a pathological process associated with various forms of heart failure. This study identified latent transforming growth factor-? binding protein 2, cartilage oligomeric matrix protein, and cartilage intermediate layer protein 1 as potential biomarkers for cardiac fibrosis. All 3 encoded proteins showed increased expression in fibroblasts after transforming growth factor-? stimulation in vitro and localized specifically to fibrotic regions in vivo. Of the 3, only the full-length cartilage intermediate layer protein 1 showed a significant decrease in circulating levels in patients with heart failure compared with healthy volunteers. Further studies on these 3 proteins will lead to a better understanding of their biomarker potential for cardiac fibrosis.
© 2020 The Authors.
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Impact of Bilateral Sympathetic Stellate Ganglionectomy on TGF-?1 Signaling Pathway in Rats With Chronic Volume Overload.
Front Physiol2020 ;11():375. doi: 10.3389/fphys.2020.00375.
Zhang Mingjing, Liu Xiaogang, Wu Jie, Yu Yijun, Wang Yuting, Gu Ye,
Abstract
We previously reported that bilateral sympathetic stellate ganglionectomy attenuated cardiac remodeling and fibrosis in rats with chronic volume overload. Transforming growth factor beta 1 (TGF-?1) is a polypeptide member of the transforming growth factor beta superfamily of cytokines and actively involved in many pathological processes of cardiovascular diseases. The present study explored the impact of bilateral sympathetic stellate ganglionectomy on the TGF-?1 pathway in this model. Male Sprague-Dawley rats were randomly divided into sham (S) group, abdominal aorta-cava fistula (AV) group, and bilateral sympathetic stellate ganglionectomy after abdominal aorta-cava fistula (AD) group. Twelve weeks after the abdominal aorta-cava fistula surgery, the myocardial expressions of norepinephrine (NE) and hydroxyproline were significantly higher, while acetylcholine was downregulated in the AV group compared to the S group; the above changes were partly reversed in the AD group. The myocardial expression of TGF-?1 and activity of Smad2/3 phosphorylation were also upregulated in the AV group compared to the S group, which could be reversed by bilateral sympathetic stellate ganglionectomy. , the TGF-?1 expression in cultured myocardial fibroblasts and the proliferation of myocardial fibroblasts were significantly increased post-stimulation with NE in a dose-dependent manner, and these effects could be blunted by co-treatment with a TGF-?1 inhibitor. Our study results indicate that stellate ganglionectomy decreases cardiac norepinephrine release, which leads to decreased TGF-?1 release and reduced fibrosis in rats with chronic volume overload.
Copyright © 2020 Zhang, Liu, Wu, Yu, Wang and Gu.
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Exendin-4 Attenuates Remodeling in the Remote Myocardium of Rats After an Acute Myocardial Infarction by Activating ?-Arrestin-2, Protein Phosphatase 2A, and Glycogen Synthase Kinase-3 and Inhibiting ?-Catenin.
Cardiovasc Drugs Ther2020 May;():. doi: 10.1007/s10557-020-07006-9.
Eid Refaat A, Khalil Mohammad Adnan, Alkhateeb Mahmoud A, Eleawa Samy M, Zaki Mohamed Samir Ahmed, El-Kott Attalla Farag, Al-Shraim Mubarak, El-Sayed Fahmy, Eldeen Muhammad Alaa, Bin-Meferij Mashael Mohammed, Awaji Khalid M E, Shatoor Abdullah S,
Abstract
PURPOSE:
This study tested if the protective anti-remodeling effect of GLP-1 agonist Exendin-4 after an acute myocardial infarction (MI) in rats involves inhibition of the Wnt1/?-catenin signaling pathway.
METHODS:
Rats were divided into sham, sham + Exendin-4 (10 ?g/day, i.p), MI, and MI + Exendin-4. MI was introduced to rats by permanent left anterior descending coronary artery (LAD) ligation.
RESULTS:
On day 7 post-infraction, MI rats showed LV dysfunction with higher serum levels of cardiac markers. Their remote myocardia showed increased mRNA and protein levels of collagen I/III with higher levels of reactive oxygen species (ROS) and inflammatory cytokines, as well as protein levels of Wnt1, phospho-Akt, transforming growth factor (TGF-?1), Smad, phospho-Smad3, ?-SMA, caspase-3, and Bax. They also showed higher protein levels of phospho-glycogen synthase kinase-3? (p-GSK3?), as well as total, phosphorylated, and nuclear ?-catenin with a concomitant decrease in the levels of cyclic adenosine monophosphate (cAMP), mRNA of manganese superoxide dismutase (MnSOD), and protein levels of Bcl-2, ?-arrestin-2, and protein phosphatase-2 (PP2A). Administration of Exendin-4 to MI rats reduced the infarct size and reversed the aforementioned signaling molecules without altering protein levels of TGF-1? and Wnt1 or Akt activation. Interestingly, Exendin-4 increased mRNA levels of MnSOD, protein levels of ?-arrestin-2 and PP2A, and ?-catenin phosphorylation but reduced the phosphorylation of GSK3? and Smad3, and total ?-catenin levels in the LV of control rats.
CONCLUSION:
Exendin-4 inhibits the remodeling in the remote myocardium of rats following acute MI by attenuating ?-catenin activation and activating ?-arrestin-2, PP2A, and GSK3?. Graphical Abstract A graphical abstract that illustrates the mechanisms by which Exendin-4 inhibits cardiac remodeling in remote myocardium of left ventricle MI-induced rats. Mechanisms are assumed to occur in the cardiomyocytes and/or other resident cells such as fibroblast. ?-catenin activation and nuclear translocation are associated with increased synthesis of inflammatory cytokines and transforming growth factor ?-1 (TGF-?1). GSK3? is inhibited by phosphorylation at Ser. Under normal conditions, ?-catenin is degraded in the cytoplasm by the active GSK3?-dependent degradation complex (un-phosphorylated) which usually phosphorylates ?-catenin at SerThr. After MI, TGF-?1, and Wnt 1 levels are significantly increased, the overproduction of Wnt1 induces ?-catenin stabilization and nuclear translocation through increasing the phosphorylation of disheveled (DVL) protein which in turn phosphorylates and inhibits GSK3?. TGF-?1 stimulates the phosphorylation of Smad-3 and subsequent nuclear translocation to activate the transcription of collage 1/III and ?-smooth muscle actin (?-SMA). Besides, TGF-?1 stabilizes cytoplasmic ?-catenin levels indirectly by phosphorylation of Akt at Thr-induced inhibition of GSK3? by increasing phosphorylation of Ser. Exendin-4, and possibly through G protein-coupled receptors (GPCRs), increases levels of cAMP and upregulates ?-arrestin-2 levels. Both can result in a positive inotropic effect. Besides, ?-arrestin-2 can stimulate PP2A to dephosphorylation Smad3 (inhibition) and GSK3? (activation), thus reduces fibrosis and prevents the activation of ?-catenin and collagen deposition.
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Epithelial-mesenchymal crosstalk in COPD: An update from in vitro model studies.
Int J Biochem Cell Biol2020 May;():105775. doi: S1357-2725(20)30092-3.
Osei Emmanuel T, Hackett Tillie-Louise,
Abstract
Chronic Obstructive Pulmonary disease (COPD) involves airway inflammation and remodeling leading to small airways disease and emphysema, which results in irreversible airflow obstruction. During lung development, reciprocal interactions between the endoderm and mesoderm (epithelial-mesenchymal trophic unit (EMTU)) are essential for morphogenetic cues that direct cell proliferation, differentiation, and extracellular (ECM) production. In COPD, a significant number of the inflammation and remodeling mediators resemble those released during lung development, which has led to the hypothesis that aberrant activation of the EMTU may occur in the disease. Studies assessing lung epithelial and fibroblast function in COPD, have been primarily focused on monoculture studies. To capture the in vivo environment of the human lung and aid in the understanding of mechanisms and mediators involved in abnormal epithelial-fibroblast communication in COPD, complex co-culture models are required. In this review, we describe the studies that have used co-culture models to assess epithelial-fibroblast interactions and their role in the pathogenesis of COPD.
Copyright © 2020. Published by Elsevier Ltd.
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Recombinant spider silk protein eADF4(C16)-RGD coatings are suitable for cardiac tissue engineering.
Sci Rep2020 May;10(1):8789. doi: 10.1038/s41598-020-65786-4.
Kramer Johannes P M, Aigner Tamara B, Petzold Jana, Roshanbinfar Kaveh, Scheibel Thomas, Engel Felix B,
Abstract
Cardiac tissue engineering is a promising approach to treat cardiovascular diseases, which are a major socio-economic burden worldwide. An optimal material for cardiac tissue engineering, allowing cardiomyocyte attachment and exhibiting proper immunocompatibility, biocompatibility and mechanical characteristics, has not yet emerged. An additional challenge is to develop a fabrication method that enables the generation of proper hierarchical structures and constructs with a high density of cardiomyocytes for optimal contractility. Thus, there is a focus on identifying suitable materials for cardiac tissue engineering. Here, we investigated the interaction of neonatal rat heart cells with engineered spider silk protein (eADF4(C16)) tagged with the tripeptide arginyl-glycyl-aspartic acid cell adhesion motif RGD, which can be used as coating, but can also be 3D printed. Cardiomyocytes, fibroblasts, and endothelial cells attached well to eADF4(C16)-RGD coatings, which did not induce hypertrophy in cardiomyocytes, but allowed response to hypertrophic as well as proliferative stimuli. Furthermore, Kymograph and MUSCLEMOTION analyses showed proper cardiomyocyte beating characteristics on spider silk coatings, and cardiomyocytes formed compact cell aggregates, exhibiting markedly higher speed of contraction than cardiomyocyte mono-layers on fibronectin. The results suggest that eADF4(C16)-RGD is a promising material for cardiac tissue engineering.
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Atorvastatin attenuates TGF??1?induced fibrogenesis by inhibiting Smad3 and MAPK signaling in human ventricular fibroblasts.
Int J Mol Med2020 May;():. doi: 10.3892/ijmm.2020.4607.
Du Yanfei, Xiao Haiying, Wan Jun, Wang Xinyu, Li Tao, Zheng Shuzhan, Feng Jian, Ye Qiang, Li Jiafu, Li Guang, Fan Zhongcai,
Abstract
Excessive proliferation and myofibroblasts transformation of cardiac fibroblasts play a critical role in the process of cardiac fibrosis. Atorvastatin (ATV), a 3?hydroxy?3?methyl?glutaryl?coenzyme A reductase inhibitor, is commonly used to treat hypercholesterolemia. It has previously been shown that ATV has potential anti?fibrotic effects. However, the underlying mechanisms of ATV against cardiac fibrosis remain to be fully elucidated, and to the best of our knowledge, there are no reports focusing on the effects of ATV on transforming growth factor??1 (TGF??1)?induced human ventricular fibroblasts (hVFs) activation. In the present study, hVFs were stimulated with TGF??1 with or without pretreatment with ATV. Subsequently, hVF proliferation, cytotoxicity, myofibroblast differentiation and pro?fibrotic gene expression were assessed. Canonical and non?canonical signaling downstream of TGF??1, such as Smad3 and mitogen?activated protein kinase (MAPK) signaling, were investigated by evaluating the phosphorylation levels of Smad3, extracellular signal?regulated kinase 1/2, p38 MAPK and c?Jun N?terminal kinase. The results indicated that ATV significantly prevented TGF??1?induced cell proliferation, myofibroblast differentiation and production of extracellular matrix proteins, such as matrix metalloproteinase?2, collagen I and collagen III, in hVFs. Furthermore, ATV effectively inhibited TGF??1?induced activation of Smad3 and MAPK signaling in hVFs. In conclusion, the present results demonstrated that ATV prevented TGF??1?induced fibrogenesis in hVFs, at least in part by inhibiting the Smad3 and MAPK signaling pathways. Therefore, these results imply that ATV may be a promising agent to treat myocardial fibrosis.
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Dissection of the HCMV-Specific Antibody Responses in Lung-Transplant Recipients.
J Heart Lung Transplant2020 Apr;39(4S):S83. doi: S1053-2498(20)31326-7.
Vietzen H, Jaksch P, Görzer I, Honsig C, Puchhammer-Stöckl E,
Abstract
PURPOSE:
Human Cytomegalovirus (HCMV) is an important viral pathogen in lung-transplant recipients (LTRs), which may cause generalized infection and tissue-invasive disease. The risk for HCMV-replication depends on the donor (D) and recipient (R) serostatus as well as on HCMV-specific immune responses such as HCMV-specific antibodies (AB) and NK-cells, which may limit viral spread after lung-transplantation. In this study we analyzed the glycoprotein B (gB) and pentameric complex (PC)-specific AB-responses as well as the antibodies' neutralizing and NK-cell activating effector functions following lung transplantation.
METHODS:
35 R+, 26 D+/R- LTRs, who received a lung transplant between 2013 and 2016 at the Medical University of Vienna and 134 non-transplanted control individuals were included in the study. From each transplanted patient, follow-up plasma samples were collected in a three-month interval in a one (R+) or two (D+/R-) year period post-transplantation. PC-specific as well as gB-specific IgG titers were determined by ELISA. 50% neutralizing titers were determined with epithelial cells, fibroblasts and the laboratory strain TB40E-BAC4. The NK-cell response was determined using NK92-CD16a cells in a serum-dependent focal expansion and a CD107 cytotoxicity assay.
RESULTS:
The R+ LTRs reached a higher level of gB- but not of PC-specific IgG-titers in the first year post-transplantation compared to healthy seropositive individuals (IgG1 one year post-transplantation gB: p<0.0001, PC=ns, Dunetts-Test). Functional analysis of gB-specific ABs exhibited a significantly better NK-cell activation in the LTRs than in healthy controls at all time points investigated (p<0.0001, Dunetts-Test). In contrast, PC-specific ABs showed only low level NK-cell activation and their neutralization capacity was comparable with that of healthy controls until one year post-transplantation (p=ns, Dunetts-Test). In 23/26 D+R- patients neutralizing ABs against PC developed during antiviral prophylaxis in the first year post-transplantation, independent from the occurrence of viremia, although only low level gB-titers and a weak NK-cell activation were observed, compared to R+ LTRs.
CONCLUSION:
From the present data it appears that R+ patients with pre-existing HCMV-specific ABs show a high level of NK-cell activation by gB-specific ABs.
Copyright © 2020. Published by Elsevier Inc.
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Studying the Correlation between Neutrophils and miR21 Expression: Role in Bronchiolitis Obliterans Syndrome.
J Heart Lung Transplant2020 Apr;39(4S):S473. doi: S1053-2498(20)30031-0.
Pandolfi L, Bozzini S, Frangipane V, D'Amato M, Morosini M, Rossi E, Meloni F,
Abstract
PURPOSE:
Bronchiolitis obliterans syndrome (BOS) is associated with poor long-term survival. In its pathogenesis neutrophils (NEU) are recognized as relevant players. Moreover, our group has recently showed that some microRNAs (miRs) may act as pro-fibrotic effectors in the context of BOS highlighting the role of miR21, whose expression was higher in BOS lungs respective to healthy lungs. Our aim was to assess whether activated NEU might contribute to epithelial mesenchymal transition (EMT) through the up regulation of miR21 in lung cells.
METHODS:
As in vitro models we chose A549 cell lines. We co-coltured for 72h cell lines with different conditions: NEU previously activated (NEU+); Supernatant of NEU previously activated with PMA - (SUP+); Neutrophil Elastase (NE); NEU+ / alpha-1-antitrypsin (AAT); SUP+ /AAT; NE / AAT and TGF-? as positive control. Total RNAs from treated cells was extracted and miR21 expressions were assessed by RT-PCR (using U6 as reference gene).
RESULTS:
We observed that all conditions induced significant miR21 up-regulation in both cell lines in contrast to untreated cells (p<0.01), even if NEU (2.7 fold increase vs. CTR) and NE (1.7 fold increase vs. CTR) exerted highest effect rather than SUP+ (1.53 fold increase vs. CTR). Interestingly, adding AAT this up-regulation is inhibited restoring its expression as control cells. Moreover, cells treated with all conditions showed a change in morphology from epithelial to fibroblast like, as well as TGF- ? treatment, suggesting that miR21 modulation led to EMT of cells.
CONCLUSION:
These results light new interest on a molecular mechanism underlying BOS development, and, if further confirmed suggests a possible therapeutic strategy aimed to modulate NEU in lung transplant patients using AAT.
Copyright © 2020. Published by Elsevier Inc.
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Gap-134, a Connexin43 activator, prevents age-related development of ventricular fibrosis in Scn5a mice.
Pharmacol Res2020 May;():104922. doi: S1043-6618(20)31230-5.
Patin Justine, Castro Claire, Steenman Marja, Hivonnait Agnès, Carcouët Agnès, Tessier Arnaud, Lebreton Jacques, Bihouée Audrey, Donnart Audrey, Le Marec Hervé, Baró Isabelle, Charpentier Flavien, Derangeon Mickaël,
Abstract
Down-regulation of Connexin43 (Cx43) has often been associated with the development of cardiac fibrosis. We showed previously that Scn5a heterozygous knockout mice (Scn5a), which mimic familial progressive cardiac conduction defect, exhibit an age-dependent decrease of Cx43 expression and phosphorylation concomitantly with activation of TGF-? pathway and fibrosis development in the myocardium between 45 and 60 weeks of age. The aim of this study was to investigate whether Gap-134 prevents Cx43 down-regulation with age and fibrosis development in Scn5a mice. We observed in 60-week-old Scn5a mouse heart a Cx43 expression and localization remodeling correlated with fibrosis. Chronic administration of a potent and selective gap junction modifier, Gap-134 (danegaptide), between 45 and 60 weeks, increased Cx43 expression and phosphorylation on serine 368 and prevented Cx43 delocalization. Furthermore, we found that Gap-134 prevented fibrosis despite the persistence of the conduction defects and the TGF-? canonical pathway activation. In conclusion, the present study demonstrates that the age-dependent decrease of Cx43 expression is involved in the ventricular fibrotic process occurring in Scn5a mice. Finally, our study suggests that gap junction modifier, such as Gap-134, could be an effective anti-fibrotic agent in the context of age-dependent fibrosis in progressive cardiac conduction disease.
Copyright © 2020 Elsevier Ltd. All rights reserved.
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Sirtuin 3 is essential for hypertension-induced cardiac fibrosis via mediating pericyte transition.
J Cell Mol Med2020 May;():. doi: 10.1111/jcmm.15437.
Su Han, Zeng Heng, Liu Bo, Chen Jian-Xiong,
Abstract
Hypertension is the key factor for the development of cardiac fibrosis and diastolic dysfunction. Our previous study showed that knockout of sirtuin 3 (SIRT3) resulted in diastolic dysfunction in mice. In the present study, we explored the role of SIRT3 in angiotensin II (Ang-II)-induced cardiac fibrosis and pericyte-myofibroblast transition. NG2 tracing reporter NG2-DsRed mouse was crossed with wild-type (WT) mice and SIRT3KO mice. Cardiac function, cardiac fibrosis and reactive oxygen species (ROS) were measured. Mice infused with Ang-II for 28 days showed a significant reduction of SIRT3 expression in the mouse hearts. Knockout of SIRT3 sensitized Ang-II-induced elevation of isovolumic relaxation time (IVRT) and reduction of ejection fraction (EF) and fractional shortening (FS). Ang-II-induced cardiac fibrosis, capillary rarefaction and hypertrophy were further enhanced by knockout of SIRT3. NG2 pericyte tracing reporter mice infused with Ang-II had a significantly increased number of NG2-DsRed pericyte in the heart. Knockout of SIRT3 further enhanced Ang-II-induced increase of pericytes. To examine pericyte-myofibroblast/fibroblast transition, DsRed pericytes were co-stained with FSP-1 and ?-SMA. Ang-II infusion led to a significant increase in numbers of DsRed /FSP-1 and DsRed /?-SMA cells, while SIRT3KO further developed pericyte-myofibroblast/fibroblast transition. In addition, knockout of SIRT3 promoted Ang-II-induced NADPH oxidase-derived ROS formation together with increased expression of transforming growth factor beta 1 (TGF-?1). We concluded that Ang-II induced cardiac fibrosis partly by the mechanisms involving SIRT3-mediated pericyte-myofibroblast/fibroblast transition and ROS-TGF-?1 pathway.
© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
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Glucocorticoid Regulates Mesenchymal Cell Differentiation Required for Perinatal Lung Morphogenesis and Function.
Am J Physiol Lung Cell Mol Physiol2020 May;():. doi: 10.1152/ajplung.00459.2019.
Bridges James P, Sudha Parvathi, Lipps Dakota, Wagner Andrew, Guo Minzhe, Du Yina, Brown Kari, Filuta Alyssa, Kitzmiller Joseph A, Stockman Courtney, Chen Xiaoting, Weirauch Matthew T, Jobe Alan H, Whitsett Jeffrey A, Xu Yan,
Abstract
While antenatal glucocorticoids are widely used to enhance lung function in preterm infants, cellular and molecular mechanisms by which glucocorticoid receptor (GR) signaling influences lung maturation remain poorly understood. Deletion of the glucocorticoid receptor gene (Nr3c1) from fetal pulmonary mesenchymal cells phenocopied defects caused by global Nr3c1 deletion, while lung epithelial- or endothelial-specific Nr3c1 deletion did not impair lung function at birth. We integrated genome-wide gene expression profiling, ATAC-seq, and single cell RNA-seq data in mice in which GR was deleted or activated to identify the cellular and molecular mechanisms by which glucocorticoids control prenatal lung maturation. GR enhanced differentiation of a newly defined proliferative mesenchymal progenitor cell (PMP) into matrix fibroblasts (MFB), in part by directly activating extracellular matrix-associated target genes, including Fn1, Col16a4, and Eln and by modulating VEGF, JAK-STAT and WNT signaling. Loss of mesenchymal GR signaling blocked fibroblast progenitor differentiation into mature MFB, which in turn increased proliferation of SOX9 alveolar epithelial progenitor cells and inhibited differentiation of mature alveolar type II (AT2) and AT1 cells. GR signaling controls genes required for differentiation of a subset of proliferative mesenchymal progenitors into matrix fibroblasts in turn, regulating signals controlling AT2/AT1 progenitor cell proliferation and differentiation, identifying cells and processes by which glucocorticoid signaling regulates fetal lung maturation.
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Human-iPSC-Derived Cardiac Stromal Cells Enhance Maturation in 3D Cardiac Microtissues and Reveal Non-cardiomyocyte Contributions to Heart Disease.
Cell Stem Cell2020 May;():. doi: S1934-5909(20)30202-2.
Giacomelli Elisa, Meraviglia Viviana, Campostrini Giulia, Cochrane Amy, Cao Xu, van Helden Ruben W J, Krotenberg Garcia Ana, Mircea Maria, Kostidis Sarantos, Davis Richard P, van Meer Berend J, Jost Carolina R, Koster Abraham J, Mei Hailiang, Míguez David G, Mulder Aat A, Ledesma-Terrón Mario, Pompilio Giulio, Sala Luca, Salvatori Daniela C F, Slieker Roderick C, Sommariva Elena, de Vries Antoine A F, Giera Martin, Semrau Stefan, Tertoolen Leon G J, Orlova Valeria V, Bellin Milena, Mummery Christine L,
Abstract
Cardiomyocytes (CMs) from human induced pluripotent stem cells (hiPSCs) are functionally immature, but this is improved by incorporation into engineered tissues or forced contraction. Here, we showed that tri-cellular combinations of hiPSC-derived CMs, cardiac fibroblasts (CFs), and cardiac endothelial cells also enhance maturation in easily constructed, scaffold-free, three-dimensional microtissues (MTs). hiPSC-CMs in MTs with CFs showed improved sarcomeric structures with T-tubules, enhanced contractility, and mitochondrial respiration and were electrophysiologically more mature than MTs without CFs. Interactions mediating maturation included coupling between hiPSC-CMs and CFs through connexin 43 (CX43) gap junctions and increased intracellular cyclic AMP (cAMP). Scaled production of thousands of hiPSC-MTs was highly reproducible across lines and differentiated cell batches. MTs containing healthy-control hiPSC-CMs but hiPSC-CFs from patients with arrhythmogenic cardiomyopathy strikingly recapitulated features of the disease. Our MT model is thus a simple and versatile platform for modeling multicellular cardiac diseases that will facilitate industry and academic engagement in high-throughput molecular screening.
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
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Epithelial-interleukin-1 inhibits collagen formation by airway fibroblasts: Implications for asthma.
Sci Rep2020 May;10(1):8721. doi: 10.1038/s41598-020-65567-z.
Osei Emmanuel T, B Mostaço-Guidolin Leila, Hsieh Aileen, Warner Stephanie M, Al-Fouadi May, Wang Mary, Cole Darren J, Maksym Geoffrey N, S Hallstrand Teal, Timens Wim, Brandsma Corry-Anke, Heijink Irene H, Hackett Tillie-Louise,
Abstract
In asthma, the airway epithelium has an impaired capacity to differentiate and plays a key role in the development of airway inflammation and remodeling through mediator release. The study objective was to investigate the release of (IL)-1 family members from primary airway epithelial-cells during differentiation, and how they affect primary airway fibroblast (PAF)-induced inflammation, extracellular matrix (ECM) production, and collagen I remodeling. The release of IL-1?/? and IL-33 during airway epithelial differentiation was assessed over 20-days using air-liquid interface cultures. The effect of IL-1 family cytokines on airway fibroblasts grown on collagen-coated well-plates and 3-dimensional collagen gels was assessed by measurement of inflammatory mediators and ECM proteins by ELISA and western blot, as well as collagen fiber formation using non-linear optical microscopy after 24-hours. The production of IL-1? is elevated in undifferentiated asthmatic-PAECs compared to controls. IL-1?/? induced fibroblast pro-inflammatory responses (CXCL8/IL-8, IL-6, TSLP, GM-CSF) and suppressed ECM-production (collagen, fibronectin, periostin) and the cell's ability to repair and remodel fibrillar collagen I via LOX, LOXL1 and LOXL2 activity, as confirmed by inhibition with ?-aminopropionitrile. These data support a role for epithelial-derived-IL-1 in the dysregulated repair of the asthmatic-EMTU and provides new insights into the contribution of airway fibroblasts in inflammation and airway remodeling in asthma.
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Transforming Growth Factor Beta3 is Required for Cardiovascular Development.
J Cardiovasc Dev Dis2020 May;7(2):. doi: E19.
Chakrabarti Mrinmay, Al-Sammarraie Nadia, Gebere Mengistu G, Bhattacharya Aniket, Chopra Sunita, Johnson John, Peña Edsel A, Eberth John F, Poelmann Robert E, Gittenberger-de Groot Adriana C, Azhar Mohamad,
Abstract
Transforming growth factor beta3 () gene mutations in patients of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD1) and Loeys-Dietz syndrome-5 (LDS5)/Rienhoff syndrome are associated with cardiomyopathy, cardiac arrhythmia, cardiac fibrosis, cleft palate, aortic aneurysms, and valvular heart disease. Although the developing heart of embryos express , its overarching role remains unclear in cardiovascular development and disease. We used histological, immunohistochemical, and molecular analyses of fetuses and compared them to wildtype littermate controls. The cardiovascular phenotypes were diverse with approximately two thirds of the fetuses having one or more cardiovascular malformations, including abnormal ventricular myocardium (particularly of the right ventricle), outflow tract septal and alignment defects, abnormal aortic and pulmonary trunk walls, and thickening of semilunar and/or atrioventricular valves. Ventricular septal defects (VSD) including the perimembranous VSDs were observed in fetuses with myocardial defects often accompanied by the muscular type VSD. studies using TGF?3-deficient fibroblasts in 3-D collagen lattice formation assays indicated that TGF?3 was required for collagen matrix reorganization. Biochemical studies indicated the 'paradoxically' increased activation of canonical (SMAD-dependent) and noncanonical (MAP kinase-dependent) pathways. TGF?3 is required for cardiovascular development to maintain a balance of canonical and noncanonical TGF? signaling pathways.
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Neutrophils Modulate Fibroblast Function and Promote Healing and Scar Formation after Murine Myocardial Infarction.
Int J Mol Sci2020 May;21(10):. doi: E3685.
Curaj Adelina, Schumacher David, Rusu Mihaela, Staudt Mareike, Li Xiaofeng, Simsekyilmaz Sakine, Jankowski Vera, Jankowski Joachim, Dumitra?cu Andreea Ramona, Hausenloy Derek J, Schuh Alexander, Liehn Elisa A,
Abstract
AIM:
Recruitment of neutrophils to the heart following acute myocardial infarction (MI) initiates inflammation and contributes to adverse post-infarct left ventricular (LV) remodeling. However, therapeutic inhibition of neutrophil recruitment into the infarct zone has not been beneficial in MI patients, suggesting a possible dual role for neutrophils in inflammation and repair following MI. Here, we investigate the effect of neutrophils on cardiac fibroblast function following MI. We found that co-incubating neutrophils with isolated cardiac fibroblasts enhanced the production of provisional extracellular matrix proteins and reduced collagen synthesis when compared to control or co-incubation with mononuclear cells. Furthermore, we showed that neutrophils are required to induce the transient up-regulation of transforming growth factor (TGF)-ß1 expression in fibroblasts, a key requirement for terminating the pro-inflammatory phase and allowing the reparatory phase to form a mature scar after MI. Neutrophils are essential for both initiation and termination of inflammatory events that control and modulate the healing process after MI. Therefore, one should exercise caution when testing therapeutic strategies to inhibit neutrophil recruitment into the infarct zone in MI patients.
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Simultaneous management of disordered phosphate and iron homeostasis to correct fibroblast growth factor 23 and associated outcomes in chronic kidney disease.
Curr Opin Nephrol Hypertens2020 Jul;29(4):359-366. doi: 10.1097/MNH.0000000000000614.
Courbon Guillaume, Martinez-Calle Marta, David Valentin,
Abstract
PURPOSE OF REVIEW:
Hyperphosphatemia, iron deficiency, and anemia are powerful stimuli of fibroblast growth factor 23 (FGF23) production and are highly prevalent complications of chronic kidney disease (CKD). In this manuscript, we put in perspective the newest insights on FGF23 regulation by iron and phosphate and their effects on CKD progression and associated outcomes. We especially focus on new studies aiming to reduce FGF23 levels, and we present new data that suggest major benefits of combined corrections of iron, phosphate, and FGF23 in CKD.
RECENT FINDINGS:
New studies show that simultaneously correcting iron deficiency and hyperphosphatemia in CKD reduces the magnitude of FGF23 increase. Promising therapies using iron-based phosphate binders in CKD might mitigate cardiac and renal injury and improve survival.
SUMMARY:
New strategies to lower FGF23 have emerged, and we discuss their benefits and risks in the context of CKD. Novel clinical and preclinical studies highlight the effects of phosphate restriction and iron repletion on FGF23 regulation.
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Protective effects of rolipram on endotoxic cardiac dysfunction via inhibition of the inflammatory response in cardiac fibroblasts.
BMC Cardiovasc Disord2020 May;20(1):242. doi: 10.1186/s12872-020-01529-7.
Ji Jingjing, Liu Zhifeng, Hong Xinxin, Liu Zheying, Gao Jinghua, Liu Jinghua,
Abstract
BACKGROUND:
Cardiac fibroblasts, regarded as the immunomodulatory hub of the heart, have been thought to play an important role during sepsis-induced cardiomyopathy (SIC). However, the detailed molecular mechanism and targeted therapies for SIC are still lacking. Therefore, we sought to investigate the likely protective effects of rolipram, an anti-inflammatory drug, on lipopolysaccharide (LPS)-stimulated inflammatory responses in cardiac fibroblasts and on cardiac dysfunction in endotoxic mice.
METHOD:
Cardiac fibroblasts were isolated and stimulated with 1??g/ml LPS for 6?h, and 10??mol/l rolipram was administered for 1?h before LPS stimulation. mRNA levels of tumor necrosis factor-? (TNF-?), interleukin-6 (IL-6) and interleukin-1? (IL-1?) in fibroblasts and their protein concentrations in supernatant were measured with real-time PCR (rt-PCR) and enzyme-linked immunosorbent assay, respectively. The expression of dual specificity phosphatase 1 (DUSP1), an endogenous negative regulator that inactivates MAPK-mediated inflammatory pathways, was also measured by rt-PCR and western blotting. DUSP1-targeted small interfering RNA (siRNA) was used to examine the specific role of DUSP1. To evaluate the role of rolipram in vivo, an endotoxic mouse model was established by intraperitoneal injection of 15?mg/kg LPS, and 10?mg/kg rolipram was intraperitoneally injected 1?h before LPS injection. mRNA and protein levels of inflammatory cytokines and DUSP1 in heart, inflammatory cell infiltration and cardiac function were all examined at 6?h after LPS injection.
RESULTS:
The results showed that LPS could increase the expression and secretion of inflammatory cytokines and decrease the transcription and expression of DUSP1 in cardiac fibroblasts. However, rolipram pretreatment significantly reversed the LPS-induced downregulation of DUSP1 and inhibited LPS-induced upregulation and secretion of TNF-? and IL-6 but not IL-1?. Moreover, DUSP1-targeted siRNA experiments indicated that the protective effect of rolipram on inflammatory response was specific dependent on DUSP1 expression. Moreover, rolipram could further reduce inflammatory cell infiltration scores as shown by pathological analysis and increase the ejection fraction (EF) detected with echocardiography in the hearts of endotoxic mice.
CONCLUSIONS:
Rolipram could improve endotoxin-induced cardiac dysfunction by upregulating DUSP1 expression to inhibit the inflammatory response in cardiac fibroblasts, which may be a potential treatment for SIC.
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Quantification of uncertainty in a new network model of pulmonary arterial adventitial fibroblast pro-fibrotic signalling.
Philos Trans A Math Phys Eng Sci2020 Jun;378(2173):20190338. doi: 10.1098/rsta.2019.0338.
Wang Ariel, Cao Shulin, Aboelkassem Yasser, Valdez-Jasso Daniela,
Abstract
Here, we present a novel network model of the pulmonary arterial adventitial fibroblast (PAAF) that represents seven signalling pathways, confirmed to be important in pulmonary arterial fibrosis, as 92 reactions and 64 state variables. Without optimizing parameters, the model correctly predicted 80% of 39 results of input-output and inhibition experiments reported in 20 independent papers not used to formulate the original network. Parameter uncertainty quantification (UQ) showed that this measure of model accuracy is robust to changes in input weights and half-maximal activation levels (EC), but is more affected by uncertainty in the Hill coefficient (), which governs the biochemical cooperativity or steepness of the sigmoidal activation function of each state variable. Epistemic uncertainty in model structure, due to the reliance of some network components and interactions on experiments using non-PAAF cell types, suggested that this source of uncertainty had a smaller impact on model accuracy than the alternative of reducing the network to only those interactions reported in PAAFs. UQ highlighted model parameters that can be optimized to improve prediction accuracy and network modules where there is the greatest need for new experiments. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.
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Cardiac fibroblast diversity in health and disease.
Matrix Biol2020 May;():. doi: S0945-053X(20)30054-8.
Soliman Hesham, Rossi Fabio M V,
Abstract
The cardiac stroma plays essential roles in health and following cardiac damage. The major player of the stroma with respect to extracellular matrix deposition, maintenance and remodeling is the poorly defined fibroblast. It has long been recognized that there is considerable variability to the fibroblast phenotype. With the advent of new, high throughput analytical methods our understanding and appreciation of this heterogeneity has grown dramatically. This review aims to explore the diversity of cardiac fibroblasts and highlights new insights into the diverse nature of these cells and their progenitors as revealed by single cell sequencing and fate mapping studies. We propose that at least in part, the observed heterogeneity is related to the existence of a differentiation cascade within stromal cells. Beyond in-organ heterogeneity, we also discuss how the stromal response to damage differs between non-regenerating organs such as the heart and regenerating organs such as skeletal muscle. In exploring possible causes for these differences, we outline that although fibrogenic cells from different organs overlap in many properties, they still possess organ-specific transcriptional signatures and differentiation biases that make them functionally distinct.
Copyright © 2020. Published by Elsevier B.V.
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Cardiac Fibroblast Activation during Myocardial Infarction Wound Healing: Fibroblast polarization after MI.
Matrix Biol2020 May;():. doi: S0945-053X(20)30039-1.
Daseke Michael J, Tenkorang Mavis A A, Chalise Upendra, Konfrst Shelby R, Lindsey Merry L,
Abstract
Cardiac wound healing after myocardial infarction (MI) evolves from pro-inflammatory to anti-inflammatory to reparative responses, and the cardiac fibroblast is a central player during the entire transition. The fibroblast mirrors changes seen in the left ventricle infarct by undergoing a continuum of polarization phenotypes that follow pro-inflammatory, anti-inflammatory, and pro-scar producing profiles. The development of each phenotype transition is contingent upon the MI environment into which the fibroblast enters. In this mini-review, we summarize our current knowledge regarding cardiac fibroblast activation during MI and highlight key areas where gaps remain.
Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
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