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Pubblicazioni recenti - cardiac fibroblast
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Influenza A virus modulates ACE2 expression and SARS-CoV-2 infectivity in human cardiomyocytes.
iScience2022 Dec;():105701. doi: 105701.
Wu Qian, Kumar Naresh, Lafuse William P, Santiagonunez Ahumada Omar, Saljoughian Noushin, Whetstone Elizabeth, Zani Ashley, Patton Ashley K, El Refaey Mona, Webb Amy, Pietrzak Maciej, Yu Lianbo, Kc Mahesh, Peeples Mark E, Ganesan Latha P, Yount Jacob S, Rajaram Murugesan V S,
Abstract
Influenza A virus (IAV) and SARS-CoV-2 virus are both acute respiratory viruses currently circulating in the human population. This study aims to determine the impact of IAV infection on SARS-CoV-2 pathogenesis and cardiomyocyte function. Infection of human bronchial epithelial cells (HBEC), A549 cells, lung fibroblasts (HLF), monocyte derived macrophages (MDMs), cardiac fibroblasts (HCF) and hiPSC-derived cardiomyocytes with IAV enhanced the expression of ACE2, the SARS-CoV-2 receptor. Similarly, IAV infection increased levels of ACE2 in the lungs of mice and humans. Interestingly, we detected heavily glycosylated form of ACE2 in hiPSC-CMs and poorly glycosylated ACE2 in other cell types. Also, prior IAV infection enhances SARS-CoV-2 spike protein binding and viral entry in all cell types. However, efficient SARS-CoV-2 replication was uniquely inhibited in cardiomyocytes. Glycosylation of ACE2 correlated with enzymatic conversion of its substrate Ang II, induction of eNOS and nitric oxide production, may provide a potential mechanism for the restricted SARS-CoV-2 replication in cardiomyocytes.
© 2022 The Author(s).
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The elevation of fibroblast growth factor 21 is associated with generalized periodontitis in patients with treated metabolic syndrome.
BMC Oral Health2022 Dec;22(1):570. doi: 10.1186/s12903-022-02533-3.
Sawangpanyangkura Teerat, Bandhaya Panwadee, Montreekachon Pattanin, Leewananthawet Anongwee, Phrommintikul Arintaya, Chattipakorn Nipon, Chattipakorn Siriporn C,
Abstract
BACKGROUND:
Fibroblast growth factor 21 (FGF21) is closely associated with metabolic syndrome (MetS). An alteration of FGF21 is possibly affected by periodontitis. The present study aimed to investigate the levels of serum FGF21 in MetS patients with generalized periodontitis and its association with periodontal and metabolic parameters.
METHODS:
One hundred forty-six MetS patients were recruited from the CORE (Cohort Of patients at a high Risk for Cardiovascular Events) Thailand registry. All participants received general data interviewing, periodontal examination and blood collection for measurement of FGF21 levels and biochemistry parameters. Periodontitis was defined according to the new classification and divided into two groups of localized periodontitis and generalized periodontitis.
RESULTS:
FGF21 was significantly higher in generalized periodontitis group when compared with localized periodontitis group (p? 0.05). The significant correlation was observed between FGF21 and variables including number of remaining teeth, mean clinical attachment loss, hypertriglyceridemia and low high-density lipoprotein cholesterol. The elevation of serum FGF21 was associated with presence of generalized periodontitis after adjusting of covariate factors (OR?=?27.12, p?=?0.012).
CONCLUSIONS:
The elevation of serum FGF21 might be a potential biomarker for MetS patients who have risk of generalized periodontitis.
© 2022. The Author(s).
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Porcupine inhibitor CGX1321 alleviates heart failure with preserved ejection fraction in mice by blocking WNT signaling.
Acta Pharmacol Sin2022 Dec;():. doi: 10.1038/s41401-022-01025-y.
Wu Hao, Tang Lu-Xun, Wang Xue-Mei, Li Liang-Peng, Chen Xiao-Kang, He Yan-Ji, Yang De-Zhong, Shi Yu, Shou Jia-Ling, Zhang Zong-Shu, Wang Liang, Lu Bing-Jun, An Songzhu Michael, Zeng Chun-Yu, Wang Wei Eric,
Abstract
Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, and lacks effective treatment. The aberration of WNT pathway underlies many pathological processes including cardiac fibrosis and hypertrophy, while porcupine is an acyltransferase essential for the secretion of WNT ligands. In this study we investigated the role of WNT signaling pathway in HFpEF as well as whether blocking WNT signaling by a novel porcupine inhibitor CGX1321 alleviated HFpEF. We established two experimental HFpEF mouse models, namely the UNX/DOCA model and high fat diet/L-NAME ("two-hit") model. The UNX/DOCA and "two-hit" mice were treated with CGX1321 (3?mg·kg·d) for 4 and 10 weeks, respectively. We showed that CGX1321 treatment significantly alleviated cardiac hypertrophy and fibrosis, thereby improving cardiac diastolic function and exercise performance in both models. Furthermore, both canonical and non-canonical WNT signaling pathways were activated, and most WNT proteins, especially WNT3a and WNT5a, were upregulated during the development of HEpEF in mice. CGX1321 treatment inhibited the secretion of WNT ligands and repressed both canonical and non-canonical WNT pathways, evidenced by the reduced phosphorylation of c-Jun and the nuclear translocation of ?-catenin and NFATc3. In an in vitro HFpEF model, MCM and ISO-treated cardiomyocytes, knockdown of porcupine by siRNA leads to a similar inhibitory effect on WNT pathways, cardiomyocyte hypertrophy and cardiac fibroblast activation as CGX1321 did, whereas supplementation of WNT3a and WNT5a reversed the anti-hypertrophy and anti-fibrosis effect of CGX1321. We conclude that WNT signaling activation plays an essential role in the pathogenesis of HFpEF, and porcupine inhibitor CGX1321 exerts a therapeutic effect on HFpEF in mice by attenuating cardiac hypertrophy, alleviating cardiac fibrosis and improving cardiac diastolic function.
© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.
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Cross-talk between TSC2 and the extracellular matrix controls pulmonary vascular proliferation and pulmonary hypertension.
Sci Signal2022 Dec;15(763):eabn2743. doi: 10.1126/scisignal.abn2743.
Shen Yuanjun, Goncharov Dmitry A, Pena Andressa, Baust Jeffrey, Chavez Barragan Andres, Ray Arnab, Rode Analise, Bachman Timothy N, Chang Baojun, Jiang Lifeng, Dieffenbach Paul, Fredenburgh Laura E, Rojas Mauricio, DeLisser Horace, Mora Ana L, Kudryashova Tatiana V, Goncharova Elena A,
Abstract
Increased proliferation and survival of cells in small pulmonary arteries (PAs) drive pulmonary arterial hypertension (PAH). Because cell growth mediated by the mTOR-containing mTORC1 complex is inhibited by tuberous sclerosis complex 2 (TSC2), we investigated the role of this GTPase-activating protein in PAH pathology. TSC2 abundance was decreased in remodeled small PAs and PA vascular smooth muscle cells (PAVSMCs) from patients with PAH or from rodent pulmonary hypertension (PH) models, as well as PAVSMCs maintained on substrates that reproduced pathology-induced stiffness. Accordingly, mice with smooth muscle-specific reduction in TSC2 developed PH. At the molecular level, decreased TSC2 abundance led to stiffness-induced PAVSMC proliferation, increased abundance of the mechanosensitive transcriptional coactivators YAP/TAZ, and enhanced mTOR kinase activity. Moreover, extracellular matrix (ECM) produced by TSC2-deficient PAVSMCs stimulated the proliferation of nondiseased PA adventitial fibroblasts and PAVSMCs through fibronectin and its receptor, the ?? integrin. Reconstituting TSC2 in PAVSMCs from patients with PAH through overexpression or treatment with the SIRT1 activator SRT2104 decreased YAP/TAZ abundance, mTOR activity, and ECM production, as well as inhibited proliferation and induced apoptosis. In two rodent models of PH, SRT2104 treatment restored TSC2 abundance, attenuated pulmonary vascular remodeling, and ameliorated PH. Thus, TSC2 in PAVSMCs integrates ECM composition and stiffness with pro-proliferative and survival signaling, and restoring TSC2 abundance could be an attractive therapeutic option to treat PH.
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Store-operated calcium entry via ORAI1 regulates doxorubicin-induced apoptosis and prevents cardiotoxicity in cardiac fibroblasts.
PLoS One2022 ;17(12):e0278613. doi: 10.1371/journal.pone.0278613.
Nemoto Hiroko, Umemura Masanari, Suzuki Fumina, Nagasako Akane, Nagao Kagemichi, Hidaka Yuko, Nakakaji Rina, Uchida Keiji, Suzuki Shinichi, Masuda Munetaka, Ishikawa Yoshihiro,
Abstract
Despite exhibiting cardiotoxicity, doxorubicin (DOX) is widely used for cancer treatments. Cardiac fibroblasts (CFs) are important in the pathogenesis of heart failure. This necessitates the study of the effect of DOX on CFs. The impairment of calcium (Ca2+) homeostasis is a common mechanism of heart failure. Store-operated Ca2+ entry (SOCE) is a receptor-regulated Ca2? entry pathway that maintains calcium balance by sensing reduced calcium stores in the endoplasmic reticulum. ORAI1, a calcium channel protein and the most important component of SOCE, is highly expressed in human cardiac fibroblasts (HCFs). It is upregulated in CFs from failing ventricles. However, whether ORAI1 in HCFs is increased and/or plays a role in DOX-induced cardiotoxicity remains unknown. In this study, we aimed to elucidate the relationship between ORAI1/SOCE and DOX-induced heart failure. Induction of apoptosis by DOX was characterized in HCFs. Apoptosis and cell cycle analyses were performed by fluorescence-activated cell sorting (FACS). Reactive oxygen species (ROS) production was measured using fluorescence. YM-58483 was used as an ORAI1/SOCE inhibitor. ORAI1-knockdown cells were established by RNA interference. In vivo experiments were performed by intraperitoneally injecting YM-58483 and DOX into mice. We first demonstrated that DOX significantly increased the protein expression level of p53 in HCFs by western blotting. FACS analysis revealed that DOX increased early apoptosis and induced cell cycle arrest in the G2 phase in fibroblasts. DOX also increased ROS production. DOX significantly increased the expression level of ORAI1 in CFs. Both YM-58483 and ORAI1 gene knockdown attenuated DOX-induced apoptosis. Similarly, YM-58483 attenuated cell cycle arrest in the G2 phase, and ORAI1 knockdown attenuated DOX-induced ROS production in HCFs. In the animal experiment, YM-58483 attenuated DOX-induced apoptosis. In HCFs, ORAI1/SOCE regulates p53 expression and plays an important role in DOX-induced cardiotoxicity. ORAI1 may serve as a new target for preventing DOX-induced heart failure.
Copyright: © 2022 Nemoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Docosahexaenoic acid administration improves diabetes-induced cardiac fibrosis through enhancing fatty acid oxidation in cardiac fibroblast.
J Nutr Biochem2022 Dec;():109244. doi: 10.1016/j.jnutbio.2022.109244.
Qin Linhui, Mei Yingwu, An Chengcheng, Ning Rui, Zhang Haifeng,
Abstract
Diabetes mellitus can lead to various complications, including organ fibrosis. Metabolic remodeling often occurs during the development of organ fibrosis. Docosahexaenoic acid (DHA), an essential ?-3 polyunsaturated fatty acid, shows great benefits in improving cardiovascular disease and organ fibrosis, including regulating cellular metabolism. In this study, we investigated whether DHA can inhibit diabetes-induced cardiac fibrosis by regulating the metabolism of cardiac fibroblasts. Type I diabetic mice were induced by streptozotocin and after supplementation with DHA for 16 weeks, clinical indicators of serum and heart were evaluated. DHA administration significantly improved serum lipid levels, cardiac function and cardiac interstitial fibrosis, but not blood glucose levels. Subsequently, immunofluorescences, western blot and label-free quantitative proteomics methods were used to study the mechanism. The results showed that the anti-fibrotic function of DHA was achieved through regulating extracellular matrix homeostasis including ECM synthesis and degradation. Our research demonstrated DHA regulated the energy metabolism of cardiac fibroblasts, especially fatty acid oxidation, and then affected the balance of ECM synthesis and degradation. It suggested that DHA supplementation could be considered an effective adjuvant therapy for cardiac fibrosis caused by hyperglycemia.
Copyright © 2022. Published by Elsevier Inc.
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GSK126 an Inhibitor of Epigenetic Regulator EZH2 Suppresses Cardiac Fibrosis by Regulating EZH2-PAX6-CXCL10 Pathway.
Biochem Cell Biol2022 Dec;():. doi: 10.1139/bcb-2022-0224.
Aziz Shireen, Yalan Li, Raza Muhammad Ahmer, Lemin Jiao, Akram Hafiz Muhammad Bilal, Zhao Wen,
Abstract
Myocardial fibrosis is a common pathological companion of various cardiovascular diseases. To date, the role of enhancer of zeste homolog 2 (EZH2) in cancer has been well demonstrated including in renal carcinoma and its inhibitors have entered the stage of phase I/II clinical trials. However, the precise mechanism of EZH2 in cardiac diseases is largely unclear. In the current study, we first found that EZH2 expression was increased in Ang-II treated cardiac fibroblasts (CFs) and mouse heart homogenates following isoproterenol (ISO) administration for 21 days, respectively. Ang-II induces CFs activation and increased collagen-I, collagen-III, ?-SMA, EZH2, and trimethylates lysine 27 on histone 3 (H3K27me3) expressions can be reversed by EZH2 inhibitor (GSK126) and EZH2 siRNA. The ISO induced-cardiac hypertrophy, and fibrosis in vivo which were also related to the upregulation of EZH2 and its downstream target, H3K27me3, could be recovered by GSK126. Furthermore, the upregulation of EZH2 induces the decrease of paired box 6 (PAX6) and C-X-C motif ligand 10 (CXCL10) "which" was also reversed by GSK126 treatment. In summary, the present evidence strongly suggests that GSK126 could be a therapeutic intervention blunting the development and progression of myocardial fibrosis in an EZH2-PAX6-CXCL10-dependent manner.
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Knockdown of Ift88 in fibroblasts causes extracellular matrix remodeling and decreases conduction velocity in cardiomyocyte monolayers.
Front Physiol2022 ;13():1057200. doi: 1057200.
Ernault Auriane C, Kawasaki Makiri, Fabrizi Benedetta, Montañés-Agudo Pablo, Amersfoorth Shirley C M, Al-Shama Rushd F M, Coronel Ruben, De Groot Joris R,
Abstract
Atrial fibrosis plays an important role in the development and persistence of atrial fibrillation by promoting reentry. Primary cilia have been identified as a regulator of fibroblasts (FB) activation and extracellular matrix (ECM) deposition. We hypothesized that selective reduction of primary cilia causes increased fibrosis and facilitates reentry. The aim of this study was to disrupt the formation of primary cilia in FB and examine its consequences on ECM and conduction in a co-culture system of cardiomyocytes (CM) and FB. Using short interfering RNA (siRNA), we removed primary cilia in neonatal rat ventricular FB by reducing the expression of gene required for ciliary assembly. We co-cultured neonatal rat ventricular cardiomyocytes (CM) with FB previously transfected with siRNA (siIft88) or negative control siRNA (siNC) for 48 h. We examined the consequences of ciliated fibroblasts reduction on conduction and tissue remodeling by performing electrical mapping, microelectrode, and gene expression measurements. Transfection of FB with siIft88 resulted in a significant 60% and 30% reduction of relative expression in FB and CM-FB co-cultures, respectively, compared to siNC. Knockdown of significantly increased the expression of ECM genes , and by 38%, 30% and 18%, respectively, in comparison to transfection with siNC. Conduction velocity (CV) was significantly decreased in the siIft88 group in comparison to siNC [11.12 ± 4.27 cm/s ( = 10) vs. 17.00 ± 6.20 ( = 10) respectively,
Copyright © 2022 Ernault, Kawasaki, Fabrizi, Montañés-Agudo, Amersfoorth, Al-Shama, Coronel and De Groot.
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Blocking VCAM-1 ameliorates hypertensive cardiac remodeling by impeding macrophage infiltration.
Front Pharmacol2022 ;13():1058268. doi: 1058268.
Qiu Ze-Yang, Yu Wei-Jia, Bai Jie, Lin Qiu-Yue,
Abstract
Cardiac remodeling is an important mechanism of heart failure, which frequently results from leukocyte infiltration. Vascular cellular adhesion molecule-1 (VCAM-1) plays a critical role in leukocyte adhesion and transmigration. However, the importance of VCAM-1 in the development of angiotensin II (Ang II)-induced cardiac remodeling remains unclear. Wild-type (WT) mice were infused with Ang II (1,000 ng/kg/min) for 14 days and simultaneously treated with VCAM-1 neutralizing antibody (0.1 or 0.2 mg) or IgG control. Systolic blood pressure (SBP) and cardiac function were detected by a tail-cuff and echocardiography. Cardiac remodeling was evaluated by histological staining. Adhesion and migration of bone marrow macrophages (BMMs) were evaluated . Our results indicated that VCAM-1 levels were increased in the serum of patients with heart failure (HF) and the hearts of Ang II-infused mice. Furthermore, Ang II-caused hypertension, cardiac dysfunction, hypertrophy, fibrosis, infiltration of VLA-4+ BMMs and oxidative stress were dose-dependently attenuated in mice administered VCAM-1 neutralizing antibody. In addition, blocking VCAM-1 markedly alleviated Ang II-induced BMMs adhesion and migration, therefore inhibited cardiomyocyte hypertrophy and fibroblast activation. In conclusion, the data reveal that blocking VCAM-1 ameliorates hypertensive cardiac remodeling by impeding VLA-4+ macrophage infiltration. Selective blockage of VCAM-1 may be a novel therapeutic strategy for hypertensive cardiac diseases.
Copyright © 2022 Qiu, Yu, Bai and Lin.
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Development of potent and selective FAAH inhibitors with improved drug-like properties as potential tools to treat neuroinflammatory conditions.
Eur J Med Chem2022 Nov;246():114952. doi: 10.1016/j.ejmech.2022.114952.
Papa Alessandro, Pasquini Silvia, Galvani Francesca, Cammarota Mariarosaria, Contri Chiara, Carullo Gabriele, Gemma Sandra, Ramunno Anna, Lamponi Stefania, Gorelli Beatrice, Saponara Simona, Varani Katia, Mor Marco, Campiani Giuseppe, Boscia Francesca, Vincenzi Fabrizio, Lodola Alessio, Butini Stefania,
Abstract
The neuroprotective performance against neuroinflammation of the endocannabinoid system (ECS) can be remarkably improved by indirect stimulation mediated by the pharmacological inhibition of the key ECS catabolic enzyme fatty acid amide hydrolase (FAAH). Based on our previous works and aiming to discover new selective FAAH inhibitors , we herein reported a new series of carbamate-based FAAH inhibitors (4a-t) which showed improved drug disposition properties compared to the previously reported analogues 2a-b. The introduction of ionizable functions allowed us to obtain new FAAH inhibitors of nanomolar potency characterized by good water solubility and chemical stability at physiological pH. Interesting structure-activity relationships (SARs), deeply analyzed by molecular docking and molecular dynamic (MD) simulations, were obtained. All the newly developed inhibitors showed an excellent selectivity profile evaluated against monoacylglycerol lipase and cannabinoid receptors. The reversible mechanism of action was determined by a rapid dilution assay. Absence of toxicity was confirmed in mouse fibroblasts NIH3T3 (for compounds 4e, 4g, 4n-o, and 4s) and in human astrocytes cell line 1321N1 (for compounds 4e, 4n, and 4s). The absence of undesired cardiac effects was also confirmed for compound 4n. Selected analogues (compounds 4e, 4g, 4n, and 4s) were able to reduce oxidative stress in 1321N1 astrocytes and exhibited notable neuroprotective effects when tested in an ex vivo model of neuroinflammation.
Copyright © 2022 Elsevier Masson SAS. All rights reserved.
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Membrane Estrogen Receptor Beta is Sufficient to Mitigate Cardiac Cell Pathology.
Endocrinology2022 Dec;():. doi: bqac200.
Ahluwalia Amrita, Hoa Neil, Moreira Debbie, Aziz Daniel, Singh Karanvir, Patel Khushin N, Levin Ellis R,
Abstract
Estrogen acting through estrogen receptor beta has been shown to oppose the stimulation of cardiac myocytes and cardiac fibroblasts that results in cardiac hypertrophy and fibrosis. Previous work has implicated signal transduction from ER? as being important to the function of estrogen in these regards. Here we address whether membrane ER? is sufficient to oppose key mechanisms by which Angiotensin II stimulates cardiac cell pathology. To do this we first defined essential structural elements within ER? that are necessary for membrane or nuclear localization in cells. We previously determined that cysteine 418 is the site of palmitoylation of ER? that is required and sufficient for cell membrane localization in mice and is the same site in humans. Here we determined in CHO cells, and mouse and rat myocytes and cardiac fibroblasts, the impact on multiple aspects of signal transduction by expressing wild type or a C418A mutant ER?. To test the importance of the nuclear receptor, we determined a four amino acid deletion in the E domain of ER? that strongly blocked nuclear localization. Using these tools, we expressed wild type and mutant ER? constructs into cardiomyocytes and cardiac fibroblasts from ER? deleted mice. We determined the ability of estrogen to mitigate cell pathology stimulated by Angiotensin II and whether the membrane ER? is necessary and sufficient.
Published by Oxford University Press on behalf of the Endocrine Society 2022.
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Eplerenone inhibits the macrophage-to-myofibroblast transition in rats with UUO-induced type 4 cardiorenal syndrome through the MR/CTGF pathway.
Int Immunopharmacol2022 Dec;113(Pt A):109396. doi: 10.1016/j.intimp.2022.109396.
Han Yutong, Xian Yunqian, Gao Xiaomeng, Qiang Panpan, Hao Juan, Yang Fan, Shimosawa Tatsuo, Chang Yi, Xu Qingyou,
Abstract
Cardiovascular complications are the leading causes of death in patients with chronic kidney disease (CKD), accounting for approximately 50% of deaths. Despite significant advances in the understanding of cardiac disease due to CKD, the underlying mechanisms involved in many pathological changes have not been fully elucidated. In our previous study, we observed severe fibrosis in the contralateral kidney of a 6-month-old rat UUO model. In the present experiment, we also observed severe fibrosis in the hearts of rats subjected to UUO and the macrophage-to-myofibroblast transition (MMT). These effects were inhibited by the mineralocorticoid receptor (MR) blocker eplerenone. Notably, in vitro, aldosterone-activated MR induced the MMT and subsequently promoted the secretion of CTGF, the target of MR, from macrophages; these changes were inhibited by eplerenone. The CTGF also induced the MMT and both the aldosterone and CTGF-induced MMT could be alleviated by the CTGF blocker. In conclusion, our results suggest that targeting the MR/CTGF pathway to inhibit the MMT may be an effective therapeutic strategy for the treatment of cardiac fibrosis.
Copyright © 2022 Elsevier B.V. All rights reserved.
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Human cytomegalovirus induces neuronal enolase to support virally mediated metabolic remodeling.
Proc Natl Acad Sci U S A2022 Dec;119(49):e2205789119. doi: 10.1073/pnas.2205789119.
Moreno Isreal, Rodríguez-Sánchez Irene, Schafer Xenia, Munger Joshua,
Abstract
Viruses depend on cellular metabolic resources to supply the energy and biomolecular building blocks necessary for their replication. Human cytomegalovirus (HCMV), a leading cause of birth defects and morbidity in immunosuppressed individuals, induces numerous metabolic activities that are important for productive infection. However, many of the mechanisms through which these metabolic activities are induced and how they contribute to infection are unclear. We find that HCMV infection of fibroblasts induces a neuronal gene signature as well as the expression of several metabolic enzyme isoforms that are typically expressed in other tissue types. Of these, the most substantially induced glycolytic gene was the neuron-specific isoform of enolase 2 (ENO2). Induction of ENO2 expression is important for HCMV-mediated glycolytic activation as well as for the virally induced remodeling of pyrimidine-sugar metabolism, which provides the glycosyl subunits necessary for protein glycosylation. Inhibition of ENO2 expression or activity reduced uridine diphosphate (UDP)-sugar pools, attenuated the accumulation of viral glycoproteins, and induced the accumulation of noninfectious viral particles. In addition, our data indicate that the induction of ENO2 expression depends on the HCMV U38 protein. Collectively, our data indicate that HCMV infection induces a tissue atypical neuronal glycolytic enzyme to activate glycolysis and UDP-sugar metabolism, increase the accumulation of glycosyl building blocks, and enable the expression of an essential viral glycoprotein and the production of infectious virions.
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Single-cell genomics illustrates heterogeneous phenotypes of myocardial fibroblasts under ischemic insults.
Biochem Cell Biol2022 Nov;():. doi: 10.1139/bcb-2022-0229.
Thankam Finosh G, La Vy, Agrawal Devendra K,
Abstract
Myocardial regenerative strategies are promising where the choice of ideal cell population is crucial for successful translational applications. Herein, we explored the regenerative/repair responses of infarct zone cardiac fibroblast(s) (CF) by unveiling their phenotype heterogeneity at single-cell resolution. CF were isolated from the infarct zone of Yucatan miniswine that suffered myocardial infarction, cultured under simulated ischemic and reperfusion, and grouped into control, ischemia, and ischemia/reperfusion. The single-cell RNA sequencing analysis revealed 19 unique cell clusters suggesting distinct subpopulations. The status of gene expression (log2 fold change (log2 FC) > 2 and log2 FC
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Transforming growth factor-? signaling: From tissue fibrosis to therapeutic opportunities.
Chem Biol Interact2022 Nov;():110289. doi: 10.1016/j.cbi.2022.110289.
Ren Li-Li, Li Xiao-Jun, Duan Ting-Ting, Li Zheng-Hai, Yang Jun-Zheng, Zhang Ya-Mei, Zou Liang, Miao Hua, Zhao Ying-Yong,
Abstract
Fibrosis refers to the excessive deposition of extracellular matrix components in the processes of wound repair or tissue regeneration after tissue damage. Fibrosis occurs in various organs such as lung, heart, liver, and kidney tissues, resulting in the failure of organ structural integrity and its functional impairment. It has long been thought to be relentlessly progressive and irreversible process, but both preclinical models and clinical trials in multiorgans have shown that fibrosis is a highly dynamic process. Transforming growth factor-beta (TGF-?) is a superfamily of related growth factors. Many studies have described that activation of profibrotic TGF-? signaling promotes infiltration and/or proliferation of preexisting fibroblasts, generation of myofibroblasts, extracellular matrix deposition, and inhibition of collagenolysis, which leads to fibrosis in the pathological milieu. This review describes the effect of TGF-? signaling in fibrotic-associate lung, heart, liver, and kidney tissues, followed by a detailed discussion of canonical and non-canonical TGF-? signaling pathway. In addition, this review also discusses therapeutic options by using natural products and chemical agents, for targeting tissue fibrosis via modulating TGF-? signaling to provide a more specific concept-driven therapy strategy for multiorgan fibrosis.
Copyright © 2022. Published by Elsevier B.V.
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Epigenetic control of LncRNA NEAT1 enables cardiac fibroblast pyroptosis and cardiac fibrosis.
Eur J Pharmacol2022 Nov;():175398. doi: 10.1016/j.ejphar.2022.175398.
Ding Ji-Fei, Zhou Yang, Xu Sheng-Song, Shi Kai-Hu, Sun He, Tu Bin, Song Kai, Xuan Hai-Yang, Sha Ji-Ming, Zhao Jian-Yuan, Tao Hui,
Abstract
Cardiac fibroblasts (CFs) drive extracellular matrix remodeling after inflammatory injury, leading to cardiac fibrosis and diastolic dysfunction. Recent studies described the role of epigenetics in cardiac fibrosis. Nevertheless, detailed reports on epigenetics regulating CFs pyroptosis and describing their implication in cardiac fibrosis are still unclear. Here, we found that DNMT3A reduces the expression of lncRNA Neat1 and promotes the NLRP3 axis leading to CFs pyroptosis, using cultured cells, animal models, and clinical samples to shed light on the underlying mechanism. We report that pyroptosis-related genes are increased explicitly in cardiac fibrosis tissue and LPS-treated CFs, while lncRNA Neat1 decreased. Mechanistically, we show that loss of DNMT3A or overexpression of lncRNA Neat1 in CFs after LPS treatment significantly enhances CFs pyroptosis and the production of pyroptosis-related markers in vitro. It has been demonstrated that DNMT3A can decrease lncRNA Neat1, promoting NLRP3 axis activation in CFs treated with LPS. In sum, this study is the first to identify that DNMT3A methylation decreases the expression of lncRNA Neat1 and promotes CFs pyroptosis and cardiac fibrosis, suggesting that DNMT3A and NEAT1 may function as an anti-fibrotic therapy target in cardiac fibrosis.
Copyright © 2022. Published by Elsevier B.V.
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Tropoelastin Improves Post-Infarct Cardiac Function by Increasing Scar Elastin.
Circ Res2022 Dec;():. doi: 10.1161/CIRCRESAHA.122.321123.
Hume Robert D, Kanagalingam Shaan, Deshmukh Tejas, Chen Siqi, Mithieux Suzanne M, Rashid Fairooj, Roohani Iman, Lu Juntang, Doan Tram, Graham Dinny, Clayton Zoe E, Slaughter Eugene, Kizana Eddy, Stempien-Otero April S, Brown Paula, Thomas Liza, Weiss Anthony S, Chong James J H,
Abstract
BACKGROUND:
Myocardial infarction (MI) is among the leading causes of death worldwide. Following MI, necrotic cardiomyocytes are replaced by a stiff collagen-rich scar. Compared to collagen, the extracellular matrix protein elastin has high elasticity and may have more favorable properties within the cardiac scar. We sought to improve post-MI healing by introducing tropoelastin, the soluble subunit of elastin, to alter scar mechanics early after MI.
METHODS AND RESULTS:
We developed an ultrasound-guided direct intramyocardial injection method to administer tropoelastin directly into the left ventricular anterior wall of rats subjected to induced MI. Experimental groups included shams and infarcted rats injected with either PBS vehicle control or tropoelastin. Compared to vehicle treated controls, echocardiography assessments showed tropoelastin significantly improved left ventricular ejection fraction (64.7±4.4% versus 46.0±3.1% control) and reduced left ventricular dyssynchrony (11.4±3.5 ms versus 31.1±5.8 ms control) 28 days post-MI. Additionally, tropoelastin reduced post-MI scar size (8.9±1.5% versus 20.9±2.7% control) and increased scar elastin (22±5.8% versus 6.2±1.5% control) as determined by histological assessments. Ribonucleic acid sequencing analyses of rat infarcts showed that tropoelastin injection increased genes associated with elastic fiber formation 7 days post-MI and reduced genes associated with immune response 11 days post-MI. To show translational relevance, we performed immunohistochemical analyses on human ischemic heart disease cardiac samples and showed an increase in tropoelastin within fibrotic areas. Using ribonucleic acid sequencing we also demonstrated the tropoelastin gene is upregulated in human ischemic heart disease and during human cardiac fibroblast-myofibroblast differentiation. Furthermore, we showed by immunocytochemistry that human cardiac fibroblast synthesize increased elastin in direct response to tropoelastin treatment.
CONCLUSIONS:
We demonstrate for the first time that purified human tropoelastin can significantly repair the infarcted heart in a rodent model of MI and that human cardiac fibroblast synthesize elastin. Since human cardiac fibroblasts are primarily responsible for post-MI scar synthesis, our findings suggest exciting future clinical translation options designed to therapeutically manipulate this synthesis.
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Female rats have a different healing phenotype than males after anterior cruciate ligament rupture with no intervention.
Front Med (Lausanne)2022 ;9():976980. doi: 976980.
Morris Jodie L, Letson Hayley L, Biros Erik, McEwen Peter C, Dobson Geoffrey P,
Abstract
Little is known on the sex-specific healing responses after an anterior cruciate ligament (ACL) rupture. To address this, we compared male and female Sprague-Dawley rats following non-surgical ACL rupture. Hematology, inflammation, joint swelling, range of motion, and pain-sensitivity were analyzed at various times over 31-days. Healing was assessed by histopathology and gene expression changes in the ACL remnant and adjacent joint tissues. In the first few days, males and females showed similar functional responses after rupture, despite contrasting hematology and systemic inflammatory profiles. Sex-specific differences were found in inflammatory, immune and angiogenic potential in the synovial fluid. Histopathology and increased collagen and fibronectin gene expression revealed significant tissue remodeling in both sexes. In the ACL remnant, however, Acta2 gene expression (?-SMA production) was 4-fold higher in males, with no change in females, indicating increased fibroblast-to-myofibroblast transition with higher contractile elements (stiffness) in males. Females had 80% lower Pparg expression, which further suggests reduced cellular differentiation potential in females than males. Sex differences were also apparent in the infrapatellar fat pad and articular cartilage. We conclude females and males showed different patterns of healing post-ACL rupture over 31-days, which may impact timing of reconstruction surgery, and possibly clinical outcome.
Copyright © 2022 Morris, Letson, Biros, McEwen and Dobson.
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Corrigendum to "LSD1 regulates the expressions of core cardiogenic transcription factors and cardiac genes in oxygen and glucose deprivation injured mice fibroblasts in vitro" [Exp. Cell Res. 418(2022):113228. PMID: 35688282].
Exp Cell Res2022 Nov;422(1):113435. doi: 10.1016/j.yexcr.2022.113435.
Cao Yiqiu, Dong Zhu, Yang Dongpeng, Ma Ximiao, Wang Xiaowu,
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Defining cardiac cell populations and relative cellular composition of the early fetal human heart.
PLoS One2022 ;17(11):e0259477. doi: 10.1371/journal.pone.0259477.
Dewing Jennifer M, Saunders Vinay, O'Kelly Ita, Wilson David I,
Abstract
While the adult human heart is primarily composed of cardiomyocytes, fibroblasts, endothelial and smooth muscle cells, the cellular composition during early development remains largely unknown. Reliable identification of fetal cardiac cell types using protein markers is critical to understand cardiac development and delineate the cellular composition of the developing human heart. This is the first study to use immunohistochemistry (IHC), flow cytometry and RT-PCR analyses to investigate the expression and specificity of commonly used cardiac cell markers in the early human fetal heart (8-12 post-conception weeks). The expression of previously reported protein markers for the detection of cardiomyocytes (Myosin Heavy Chain (MHC) and cardiac troponin I (cTnI), fibroblasts (DDR2, THY1, Vimentin), endothelial cells (CD31) and smooth muscle cells (?-SMA) were assessed. Two distinct populations of cTnI positive cells were identified through flow cytometry, with MHC positive cardiomyocytes showing high cTnI expression (cTnIHigh) while MHC negative non-myocytes showed lower cTnI expression (cTnILow). cTnI expression in non-myocytes was further confirmed by IHC and RT-PCR analyses, suggesting troponins are not cardiomyocyte-specific and may play distinct roles in non-muscle cells during early development. Vimentin (VIM) was expressed in cultured ventricular fibroblast populations and flow cytometry revealed VIMHigh and VIMLow cell populations in the fetal heart. MHC positive cardiomyocytes were VIMLow whilst CD31 positive endothelial cells were VIMHigh. Using markers investigated within this study, we characterised fetal human cardiac populations and estimate that 75-80% of fetal cardiac cells are cardiomyocytes and are MHC+/cTnIHigh/VIMLow, whilst non-myocytes comprise 20-25% of total cells and are MHC-/cTnILow/VIMHigh, with CD31+ endothelial cells comprising ~9% of this population. These findings show distinct differences from those reported for adult heart.
Copyright: © 2022 Dewing et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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