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Pubblicazioni recenti - cardiac fibroblast
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HDAC1 Promotes Myocardial Fibrosis in Diabetic Cardiomyopathy by Inhibiting BMP-7 Transcription Through Histone Deacetylation.
Exp Clin Endocrinol Diabetes2022 Jun;():. doi: 10.1055/a-1780-8768.
Ouyang Chun, Huang Lei, Ye Xiaoqiang, Ren Mingming, Han Zhen,
Abstract
OBJECTIVE:
Diabetic cardiomyopathy (DCM) constitutes a primary cause of mortality in diabetic patients. Histone deacetylase (HDAC) inhibition can alleviate diabetes-associated myocardial injury. This study investigated the mechanism of HDAC1 on myocardial fibrosis (MF) in DCM.
METHODS:
A murine model of DCM was established by a high-fat diet and streptozotocin injection. The bodyweight, blood glucose, serum insulin, and cardiac function of mice were analyzed. Lentivirus-packaged sh-HDAC1 was injected into DCM mice and high glucose (HG)-induced cardiac fibroblasts (CFs). The pathological structure of the myocardium and the level of myocardial fibrosis were observed by histological staining. HDAC1 expression in mouse myocardial tissues and CFs was determined. Collagen I, collagen III, alpha-smooth muscle actin (?-SMA), and vimentin levels in CFs were detected, and CF proliferation was tested. HDAC activity and histone acetylation levels in tissues and cells were measured. Bone morphogenetic protein-7 (BMP-7) expression in myocardial tissues and CFs was determined. Functional rescue experiments were conducted to confirm the effects of histone acetylation and BMP-7 on myocardial fibrosis.
RESULTS:
DCM mice showed decreased bodyweight, elevated blood glucose and serum insulin, and cardiac dysfunction. Elevated HDAC1 and reduced BMP-7 expressions were detected in DCM mice and HG-induced CFs. HDAC1 repressed BMP-7 transcription through deacetylation. HDAC1 silencing alleviated MF, reduced CF proliferation and decreased collagen I, -III, ?-SMA, and vimentin levels. However, reducing histone acetylation level or BMP-7 downregulation reversed the effects of HDAC1 silencing on CF fibrosis.
CONCLUSION:
HDAC1 repressed BMP-7 transcription by enhancing histone deacetylation, thereby promoting MF and aggravating DCM.
Thieme. All rights reserved.
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LINC01013 Is a Determinant of Fibroblast Activation and Encodes a Novel Fibroblast-Activating Micropeptide.
J Cardiovasc Transl Res2022 Jun;():. doi: 10.1007/s12265-022-10288-z.
Quaife N M, Chothani S, Schulz J F, Lindberg E L, Vanezis K, Adami E, O'Fee K, Greiner J, Litvi?uková M, van Heesch S, Whiffin N, Hubner N, Schafer S, Rackham O, Cook S A, Barton P J R,
Abstract
Myocardial fibrosis confers an almost threefold mortality risk in heart disease. There are no prognostic therapies and novel therapeutic targets are needed. Many thousands of unannotated small open reading frames (smORFs) have been identified across the genome with potential to produce micropeptides (100 amino acids). We sought to investigate the role of smORFs in myocardial fibroblast activation.Analysis of human cardiac atrial fibroblasts (HCFs) stimulated with profibrotic TGF?1 using RNA sequencing (RNA-Seq) and ribosome profiling (Ribo-Seq) identified long intergenic non-coding RNA LINC01013 as TGF?1 responsive and containing an actively translated smORF. Knockdown of LINC01013 using siRNA reduced expression of profibrotic markers at baseline and blunted their response to TGF?1. In contrast, overexpression of a codon-optimised smORF invoked a profibrotic response comparable to that seen with TGF?1 treatment, whilst FLAG-tagged peptide associated with the mitochondria.Together, these data support a novel LINC01013 smORF micropeptide-mediated mechanism of fibroblast activation.
© 2022. The Author(s).
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Research Progress of Traditional Chinese Medicine in Treatment of Myocardial fibrosis.
Front Pharmacol2022 ;13():853289. doi: 10.3389/fphar.2022.853289.
Ren Chunzhen, Liu Kai, Zhao Xinke, Guo Huan, Luo Yali, Chang Juan, Gao Xiang, Lv Xinfang, Zhi Xiaodong, Wu Xue, Jiang Hugang, Chen Qilin, Li Yingdong,
Abstract
Effective drugs for the treatment of myocardial fibrosis (MF) are lacking. Traditional Chinese medicine (TCM) has garnered increasing attention in recent years for the prevention and treatment of myocardial fibrosis. This Article describes the pathogenesis of myocardial fibrosis from the modern medicine, along with the research progress. Reports suggest that Chinese medicine may play a role in ameliorating myocardial fibrosis through different regulatory mechanisms such as reduction of inflammatory reaction and oxidative stress, inhibition of cardiac fibroblast activation, reduction in extracellular matrix, renin-angiotensin-aldosterone system regulation, transforming growth Factor-?1 (TGF-?1) expression downregulation, TGF-?1/Smad signalling pathway regulation, and microRNA expression regulation. Therefore, traditional Chinese medicine serves as a valuable source of candidate drugs for exploration of the mechanism of occurrence and development, along with clinical prevention and treatment of MF.
Copyright © 2022 Ren, Liu, Zhao, Guo, Luo, Chang, Gao, Lv, Zhi, Wu, Jiang, Chen and Li.
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Effects of high glucose and insulin on the electrophysiological properties of cardiomyocytes derived from human-induced pluripotent stem cells.
Zhong Nan Da Xue Xue Bao Yi Xue Ban2022 May;47(5):610-618. doi: 1672-7347(2022)05-0610-09.
Wei Feng, Zhang Yushun, Wang Xingye, Huo Jianhua,
Abstract
OBJECTIVES:
The risk of arrhythmia increases in diabetic patients. However, the effects of hyperglycemia and insulin therapy on the electrophysiological properties of human cardiomyocytes remain unclear. This study is to explore the effects of high glucose and insulin on the electrophysiological properties and arrhythmias of cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs).
METHODS:
Immunofluorescent staining and flow cytometry were used to analyze the purity of hiPSC-CMs generated from human skin fibroblasts of a healthy donor. The hiPSC-CMs were divided into 3 group (treated with normal medium, high glucose and insulin for 4 days): a control group (NM group, containing 5 mmol/L glucose), a high glucose group (HG group, containing 15 mmol/L glucose), and a high glucose combined with insulin (HG+INS group, containing 15 mmol/L glucose+100 mg/L insulin). Electrophysiological changes of hiPSC-CMs were detected by microelectrode array (MEA) before or after treatment with glucose and insulin, including beating rate (BR), field potential duration (FPD) (similar to QT interval in ECG), FPDc (FPD corrected by BR), spike amplitude and conduction velocity (CV). Effects of sotalol on electrophysiological properties and arrhythmias of hiPSC-CMs were also evaluated.
RESULTS:
The expression of cardiac-specific marker of cardiac troponin T was high in the hiPSC-CMs. The purity of hiPSC-CMs was 99.06%. Compared with the NM group, BR was increased by (9.14±0.8)% in the HG group (0.05). Ten µmol/L of sotalol can induce significant arrhythmias from all wells in the HG group. After treatment with insulin and high glucose, compared with the HG group, BR was increased by (8.3±0.5)% in the HG+INS group (0.05). The induction experiment showed that 10 ?mol/L of sotalol could prolong the FPDc of hiPSC-CMs by (78.9±11.6)% in the HG+INS group, but no arrhythmia was induced in each well.
CONCLUSIONS:
High glucose can induce FPD/FPDc of hiPSC-CMs prolongation and increase the risk of arrhythmia induced by drugs. Insulin can reduce the FPD/FPDc prolongation and the risk of induced arrhythmia by high glucose.These results are important to understand the electrophysiological changes of the myocardium in diabetic patients and the impact of insulin therapy on its electrophysiology. Further study on the mechanism may provide new ideas and methods for the treatment of acquired and even inherited long QT syndrome.
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Calycosin reduces myocardial fibrosis and improves cardiac function in post-myocardial infarction mice by suppressing TGFBR1 signaling pathways.
Phytomedicine2022 Jun;104():154277. doi: S0944-7113(22)00356-7.
Chen Guanghong, Xu Honglin, Xu Tong, Ding Wenjun, Zhang Guoyong, Hua Yue, Wu Yuting, Han Xin, Xie Lingpeng, Liu Bin, Zhou Yingchun,
Abstract
BACKGROUND:
Excessive myocardial fibrosis is the pathological basis of heart failure following myocardial infarction (MI). Although calycosin improves cardiac function, its effect on cardiac fibrosis and cardiac function after MI in mice and its precise mechanism remain unclear.
PURPOSE:
Here, we firstly investigated the effects of calycosin on cardiac fibrosis and ventricular function in mice after MI and the role of transforming growth factor-beta receptor 1 (TGFBR1) signaling in the amelioration of cardiac fibrosis and ventricular function.
METHODS:
In vivo effects of calycosin on cardiac structure and function in mice with MI induced by left anterior descending coronary artery ligation were determined by hematoxylin and eosin staining, Masson trichrome staining, and echocardiography. The molecular mechanism of the interaction between TGFBR1 and calycosin was investigated using molecular docking, molecular dynamics (MD) simulation, surface plasmon resonance imaging (SPRi), immunohistochemistry, and western blotting (WB). Subsequently, cardiac-specific Tgfbr1 knockout mice were used to verify the effects of calycosin. The effect of calycosin on primary cardiac fibroblasts (CFs) proliferation and collagen deposition was detected using cell counting (CCK-8), EdU assay, and WB in vitro. CFs infected with an adenovirus that encodes TGFBR1 were used to verify the effects of calycosin.
RESULTS:
In vivo, calycosin attenuated myocardial fibrosis and cardiac dysfunction following MI in a dose-dependent pattern. Calycosin-TGFBR1 complex was found to have a binding energy of -9.04 kcal/mol based on molecular docking. In addition, calycosin bound steadily in the cavity of TGFBR1 during the MD simulation. Based on SPRi results, the solution equilibrium dissociation constant for calycosin and TGFBR1 was 5.11 × 10 M. Calycosin inhibited the expression of TGFBR1, Smad2/3, collagen I, and collagen III. The deletion of TGFBR1 partially counteracted these effects. In vitro, calycosin suppressed CFs proliferation and collagen deposition after TGF-?1 stimulation by suppressing the TGFBR1 signaling pathway. The suppressive effects of calycosin were partially rescued by overexpression of TGFBR1.
CONCLUSION:
Calycosin attenuates myocardial fibrosis and cardiac dysfunction following MI in mice in vivo via suppressing the TGFBR1 signaling pathway. Calycosin suppresses CFs proliferation and collagen deposition induced by TGF-?1 via inhibition of the TGFBR1 signaling pathway in vitro.
Copyright © 2022. Published by Elsevier GmbH.
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Progressive stages of dysmetabolism are associated with impaired biological features of human cardiac stromal cells mediated by the oxidative state and autophagy.
J Pathol2022 Jun;():. doi: 10.1002/path.5985.
Francesca Pagano, Vittorio Picchio, Antonella Bordin, Elena Cavarretta, Cristina Nocella, Claudia Cozzolino, Erica Floris, Francesco Angelini, Alessia Sordano, Mariangela Peruzzi, Fabio Miraldi, Giuseppe Biondi-Zoccai, Elena De Falco, Roberto Carnevale, Sebastiano Sciarretta, Giacomo Frati, Isotta Chimenti,
Abstract
Cardiac stromal cells (CSCs) are the main players in fibrosis. Dysmetabolic conditions (metabolic syndrome - MetS, and type 2 diabetes - DM2) are strong pathogenetic contributors to cardiac fibrosis. Moreover, modulation of the oxidative state (OxSt) and autophagy is a fundamental function affecting the fibrotic commitment of CSCs, that are adversely modulated in MetS/DM2. We aimed to characterize CSCs from dysmetabolic patients, and to obtain a beneficial phenotypic setback from such fibrotic commitment by modulation of OxSt and autophagy. CSCs were isolated from 38 patients, stratified as MetS, DM2, or controls. Pharmacological modulation of OxSt and autophagy was obtained by treatment with trehalose and NOX4/NOX5 inhibitors (TREiNOX). Flow-cytometry and RT-qPCR analyses showed significantly increased expression of myofibroblasts markers in MetS-CSCs at baseline (GATA4, ACTA2, THY1/CD90) and after starvation (COL1A1, COL3A1). MetS- and DM2-CSCs displayed a paracrine profile distinct from control cells, as evidenced by heatmap analysis of 30 secreted cytokines, with significant reduction in VEGF and endoglin confirmed by ELISA. DM2-CSCs showed significantly reduced support to endothelial cells in angiogenic assays, and significantly increased H O release and NOX4/5 expression levels. Autophagy impairment after starvation (reduced ATG7 and LC3-II proteins) was also detectable in DM2-CSCs. TREiNOX treatment significantly reduced ACTA2, COL1A1, COL3A1, and NOX4 expression in both DM2- and MetS-CSCs, as well as GATA4 and THY1/CD90 in DM2, all versus control cells. Moreover, TREiNOX significantly increased VEGF release by DM2-CSCs, and VEGF and endoglin release by both MetS- and DM2-CSCs, also recovering the angiogenic support to endothelial cells by DM2-CSCs. In conclusion, DM2 and MetS worsen microenvironmental conditioning by CSCs. Appropriate modulation of autophagy and OxSt in human CSCs appears to restore these features, mostly in DM2-CSCs, suggesting a novel strategy against cardiac fibrosis in dysmetabolic patients. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
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Revealing the pathogenic and ageing-related mechanisms of the enigmatic idiopathic pulmonary fibrosis (and chronic obstructive pulmonary disease).
Curr Opin Pulm Med2022 Jul;28(4):296-302. doi: 10.1097/MCP.0000000000000876.
Spagnolo Paolo, Semenzato Umberto,
Abstract
PURPOSE OF REVIEW:
Growing evidence suggests that ageing-associated alterations occur in both idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Here, we review the most recent literature on dysregulated ageing pathways in IPF and COPD and discuss how they may contribute to disease pathogenesis.
RECENT FINDINGS:
Recent studies have shown that alveolar epithelial type II (ATII) cells undergo premature senescence under stress and that senescent ATII cells promote lung fibrogenesis. Some studies have explored the role of mitochondrial dysfunction in IPF. They have provided evidence that dysfunctional mitochondria are important contributors to fibrogenesis through release of damaged DNA and excessive formation of reactive oxygen species, whereas restoration of mitochondrial homeostasis may attenuate lung fibrosis. Insufficient autophagy has been shown to promote epithelial-to-mesenchymal transition and aberrant epithelial-fibroblast crosstalk, suggesting that autophagy augmentation may represent a potential therapeutic strategy. A number of studies have also explored the role of cellular senescence, mitochondrial homeostasis and autophagy in COPD.
SUMMARY:
Several ageing mechanisms are dysregulated in the lungs of patients with IPF and COPD, although how they contribute to disease development and progression remains elusive. Genetic or pharmacologic attenuation of senescence-related pathways and elimination of senescent cells may represent a promising therapeutic strategy.
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved .
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F-box and WD repeat-containing protein 7 ameliorates angiotensin II-induced myocardial hypertrophic injury via the mTOR-mediated autophagy pathway.
Exp Ther Med2022 Jul;24(1):464. doi: 10.3892/etm.2022.11391.
Liu Qiang, Han Chenjun, Wu Xiaoyun, Zhou Jian, Zang Wangfu,
Abstract
Myocardial hypertrophy is a common heart disease that is closely associated with heart failure. The expression of F-box and WD repeat-containing protein 7 (FBW7) is significantly downregulated in angiotensin (Ang) II-induced cardiac fibroblasts, suggesting that it may possess an important function in cardiac development. The present study attempted to explore the role of FBW7 in Ang II-induced myocardial hypertrophic injury and its associated mechanism of action. Reverse transcription-quantitative PCR and western blotting were used to determine the expression levels of FBW7 in Ang II-induced H9C2 cells. The expression levels of autophagy-related and mTOR signaling pathway-related proteins were detected using western blotting. Cell viability was assessed using the Cell Counting Kit-8 assay. The apoptosis rate of H9C2 cells was detected using TUNEL assay and western blotting. Cellular hypertrophy and fibrosis were assessed using phalloidin staining and western blotting. Levels of inflammatory factors were examined using ELISA and western blotting, whereas levels of oxidative stress-related markers were detected by corresponding kits. The results indicated that FBW7 expression was downregulated in Ang II-induced H9C2 cells. FBW7 upregulation enhanced the expression levels of autophagy-related proteins and activated mTOR-mediated cellular autophagy. FBW7 overexpression promoted the cell viability, inhibited Ang II-induced apoptosis, cellular hypertrophy and fibrosis in H9C2 cells via the autophagic pathway, as well as inflammation and oxidative stress. Overall, the data indicated that FBW7 overexpression ameliorated Ang II-induced hypertrophic myocardial injury via the mTOR-mediated autophagic pathway.
Copyright: © Liu et al.
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Surfactant-Free Chitosan/Cellulose Acetate Phthalate Nanoparticles: An Attempt to Solve the Needs of Captopril Administration in Paediatrics.
Pharmaceuticals (Basel)2022 May;15(6):. doi: 662.
Nieto González Noelia, Cerri Guido, Molpeceres Jesús, Cossu Massimo, Rassu Giovanna, Giunchedi Paolo, Gavini Elisabetta,
Abstract
The Paediatric Committee of the European Medicines Agency encourages research into medicinal products for children, in particular, the development of an age-appropriate formulation of captopril is required in the cardiovascular therapeutic area. The aim of this study was the development of a liquid formulation using nanoparticles based only on chitosan and cellulose acetate phthalate containing captopril for the treatment of hypertension, heart failure and diabetic nephropathy in paediatric patients. Nanoparticles were prepared by a nanoprecipitation method/dropping technique without using surfactants, whose use can be associated with toxicity. A range of different cellulose to chitosan weight ratios were tested. A good encapsulation efficiency (61.0 ± 6.5%) was obtained when a high chitosan concentration was used (1:3 ratio); these nanoparticles (named NP-C) were spherical with a mean diameter of 427.1 ± 32.7 nm, 0.17 ± 0.09 PDI and +53.30 ± 0.95 mV zeta potential. NP-C dispersion remained stable for 28 days in terms of size and drug content and no captopril degradation was observed. NP-C dispersion released 70% of captopril after 2 h in pH 7.4 phosphate buffer and NP-C dispersion did not have a cytotoxicity effect on neonatal human fibroblasts except at the highest dose tested after 48 h. As a result, chitosan/cellulose nanoparticles could be considered a suitable platform for captopril delivery in paediatrics for preparing solid/liquid dosage forms.
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Physiological and Pathophysiological Effects of C-Type Natriuretic Peptide on the Heart.
Biology (Basel)2022 Jun;11(6):. doi: 911.
Yasoda Akihiro,
Abstract
C-type natriuretic peptide (CNP) is the third member of the natriuretic peptide family. Unlike other members, i.e., atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), which are cardiac hormones secreted from the atrium and ventricle of the heart, respectively, CNP is regarded as an autocrine/paracrine regulator with broad expression in the body. Because of its low expression levels compared to ANP and BNP, early studies failed to show its existence and role in the heart. However, recent studies have revealed the physiological and pathophysiological importance of CNP in the heart; in concert with the distribution of its specific natriuretic peptide receptor-B (NPR-B), CNP has come to be regarded as the major heart-protective natriuretic peptide in the failed heart. NPR-B generates intracellular cyclic guanosine 3',5'-monophosphate (cGMP) upon CNP binding, followed by various molecular effects including the activation of cGMP-dependent protein kinases, which generates diverse cytoprotective actions in cardiomyocytes, as well as in cardiac fibroblasts. CNP exerts negative inotropic and positive lusitropic responses in both normal and failing heart models. Furthermore, osteocrin, the intrinsic and specific ligand for the clearance receptor for natriuretic peptides, can augment the effects of CNP and may supply a novel therapeutic strategy for cardiac protection.
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Interaction of Pacemaker Cells and Fibroblasts in the SAN. Another Way of Setting the "Clocks"?
Circ Res2022 Jun;131(1):21-23. doi: 10.1161/CIRCRESAHA.122.321336.
De Giusti Verónica C, Villa-Abrille María C, Aiello Ernesto A,
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Fibroblast Growth Factor 23 and Cardiovascular Risk in Diabetes Patients-Cardiologists Be Aware.
Metabolites2022 May;12(6):. doi: 498.
Kurpas Anna, Supel Karolina, Wieczorkiewicz Paulina, Bodalska Duleba Joanna, Zielinska Marzenna,
Abstract
Numerous clinical studies have indicated that elevated FGF23 (fibroblast growth factor 23) levels may be associated with cardiovascular (CV) mortality, especially in patients with chronic kidney disease. The purpose of this study was to examine the hypothesis that FGF23 may be a potent CV risk factor among patients with long-standing type 2 diabetes mellitus (T2DM). Research was performed utilizing patients with T2DM and regular outpatient follow-up care. Baseline characteristics determined by laboratory tests were recorded. Serum FGF23 levels were detected using a sandwich enzyme-linked immunosorbent assay. All patients underwent echocardiograms and 12-lead electrocardiograms. Data records of 102 patients (males: 57%) with a median age of 69 years (interquartile range (IQR) 66.0-74.0) were analyzed. Baseline characteristics indicated that one-third (33%) of patients suffered from ischemic heart disease (IHD), and the median time elapsed since diagnosis with T2DM was 19 years (IQR 14.0-25.0). The hemoglobin A1c, estimated glomerular filtration rate, and FGF23 values were, respectively, as follows: 6.85% (IQR 6.5-7.7), 80 mL/min/1.73 m (IQR 70.0-94.0), and 253.0 pg/mL (IQR 218.0-531.0). The study revealed that FGF23 was elevated in all patients, regardless of IHD status. Thus, the role of FGF23 as a CV risk factor should not be overestimated among patients with T2DM and good glycemic control.
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Single-nucleus profiling of human dilated and hypertrophic cardiomyopathy.
Nature2022 Jun;():. doi: 10.1038/s41586-022-04817-8.
Chaffin Mark, Papangeli Irinna, Simonson Bridget, Akkad Amer-Denis, Hill Matthew C, Arduini Alessandro, Fleming Stephen J, Melanson Michelle, Hayat Sikander, Kost-Alimova Maria, Atwa Ondine, Ye Jiangchuan, Bedi Kenneth C, Nahrendorf Matthias, Kaushik Virendar K, Stegmann Christian M, Margulies Kenneth B, Tucker Nathan R, Ellinor Patrick T,
Abstract
Heart failure encompasses a heterogeneous set of clinical features that converge on impaired cardiac contractile function and presents a growing public health concern. Previous work has highlighted changes in both transcription and protein expression in failing hearts, but may overlook molecular changes in less prevalent cell types. Here we identify extensive molecular alterations in failing hearts at single-cell resolution by performing single-nucleus RNA sequencing of nearly 600,000 nuclei in left ventricle samples from 11 hearts with dilated cardiomyopathy and 15 hearts with hypertrophic cardiomyopathy as well as 16 non-failing hearts. The transcriptional profiles of dilated or hypertrophic cardiomyopathy hearts broadly converged at the tissue and cell-type level. Further, a subset of hearts from patients with cardiomyopathy harbour a unique population of activated fibroblasts that is almost entirely absent from non-failing samples. We performed a CRISPR-knockout screen in primary human cardiac fibroblasts to evaluate this fibrotic cell state transition; knockout of genes associated with fibroblast transition resulted in a reduction of myofibroblast cell-state transition upon TGF?1 stimulation for a subset of genes. Our results provide insights into the transcriptional diversity of the human heart in health and disease as well as new potential therapeutic targets and biomarkers for heart failure.
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
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Tumor endothelial marker 1 is upregulated in heart after cardiac injury and participates in cardiac remodeling.
Sci Rep2022 Jun;12(1):10532. doi: 10.1038/s41598-022-14567-2.
Chen Po-Sheng, Feng Wen-Han, Tsai Tzu-Hsien, Hong Yi-Kai, Lee An-Sheng, Chang Kuan-Cheng, Chung Hsing-Chun, Liu Yen-Wen, Hsieh Chih-Cheng, Fang Yi-Hsian, Yang Pei-Jung, Luo Chawn-Yau, Liu Ping-Yen, Cheng Tsung-Lin, Li Yi-Heng,
Abstract
Tumor endothelial marker 1 (TEM1) is a transmembrane glycoprotein that appears on mesenchymal lineage-derived cells during embryogenesis, but its expression greatly reduces after birth. Re-upregulation of TEM1 is found in tumor angiogenesis, organ fibrosis and wound healing indicating its potential role in tissue remodeling and repair. The expression level and function of TEM1 in adult heart are unknown. In explanted hearts from heart failure (HF) patients received cardiac transplantation, immunofluorescence staining showed TEM1 was expressed in cardiomyocytes (CMs) and cardiac fibroblasts. Bioinformatics analysis showed TEM1 upregulation in mouse heart after coronary ligation. Cardiac TEM1 expression was reconfirmed in mouse HF induced by coronary ligation or doxorubicin injection. TEM1 expression increased in cultured CMs stimulated with mechanical stretch, doxorubicin and hypoxia. Further studies showed recombinant TEM1 (rTEM1) was a functional protein that influenced cell behaviors of CMs. It directly activated Erk and Akt through interaction with PDGF receptor. TEM1 mice had less collagen deposition and worse cardiac function than wild type mice. These results indicate that TEM1 expression increases in the heart after cardiac injury and works as a functional protein that participates in cardiac remodeling.
© 2022. The Author(s).
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Integrated multiomic characterization of congenital heart disease.
Nature2022 Jun;():. doi: 10.1038/s41586-022-04989-3.
Hill Matthew C, Kadow Zachary A, Long Hali, Morikawa Yuka, Martin Thomas J, Birks Emma J, Campbell Kenneth S, Nerbonne Jeanne, Lavine Kory, Wadhwa Lalita, Wang Jun, Turaga Diwakar, Adachi Iki, Martin James F,
Abstract
The heart, the first organ to develop, undergoes complex morphogenesis that when defective results in congenital heart disease (CHD). With current therapies, more than 90% of CHD patients survive into adulthood but often suffer premature death from heart failure (HF) and non-cardiac causes . To gain insight into poorly understood disease progression, we performed single nuclear RNA sequencing (snRNA-seq) and analyzed 157,273 nuclei from donors and CHD patients, including hypoplastic left heart syndrome (HLHS) and Tetralogy of Fallot (TOF), two common forms of cyanotic CHD lesions, as well as, dilated (DCM) and hypertrophic (HCM) cardiomyopathies. We observed CHD specific cell states in cardiomyocytes (CMs) which had evidence of insulin resistance and increased FOXO and CRIM1 expression. Cardiac fibroblasts (CFs) in HLHS had enrichment for a low HIPPO and high YAP cell state characteristic of activated CFs. Imaging Mass Cytometry (IMC) uncovered the spatially resolved perivascular microenvironment consistent with an immunodeficient state in CHD. Peripheral immune cell profiling suggested deficient monocytic immunity in CHD in agreement with CHD predilection to infection and cancer . Our comprehensive CHD phenotyping provides a roadmap for future personalized medicine in CHD.
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
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Fibroblast Growth Factor 23 and Chronic Kidney Disease in Children: Is It the Heart of the Matter?
Indian J Pediatr -
Postnatal Deletion of Bmal1 in Cardiomyocyte Promotes Pressure Overload Induced Cardiac Remodeling in Mice.
J Am Heart Assoc2022 Jun;():e025021. doi: 10.1161/JAHA.121.025021.
Liang Qing, Xu Hu, Liu Min, Qian Lei, Yan Jin, Yang Guangrui, Chen Lihong,
Abstract
Background Mice with cardiomyocyte-specific deletion of Bmal1, a core clock gene, had spontaneous abnormal cardiac metabolism, dilated cardiomyopathy, and shortened lifespan. However, the role of cardiomyocyte Bmal1 in pressure overload induced cardiac remodeling is unknown. Here we aimed to understand the contribution of cardiomyocyte Bmal1 to cardiac remodeling in response to pressure overload induced by transverse aortic constriction or chronic angiotensin ? (Ang?) infusion. Methods and Results By generating a tamoxifen-inducible cardiomyocyte-specific Bmal1 knockout mouse line (cKO) and challenging the mice with transverse aortic constriction or Ang?, we found that compared to littermate controls, the cKO mice displayed remarkably increased cardiac hypertrophy and augmented fibrosis both after transverse aortic constriction and Ang? induction, as assessed by echocardiographic, gravimetric, histologic, and molecular analyses. Mechanistically, RNA-sequencing analysis of the heart after transverse aortic constriction exposure revealed that the PI3K/AKT signaling pathway was significantly activated in the cKOs. Consistent with the in vivo findings, in vitro study showed that knockdown of Bmal1 in cardiomyocytes significantly promoted phenylephrine-induced cardiomyocyte hypertrophy and triggered fibroblast-to-myofibroblast differentiation, while inhibition of AKT remarkedly reversed the pro-hypertrophy and pro-fibrosis effects of Bmal1 knocking down. Conclusions These results suggest that postnatal deletion of Bmal1 in cardiomyocytes may promote pressure overload-induced cardiac remodeling. Moreover, we identified PI3K/AKT signaling pathway as the potential mechanistic ties between Bmal1 and cardiac remodeling.
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A narrative review on the biology of piezo1 with platelet-rich plasma in cardiac cell regeneration.
Chem Biol Interact2022 Jun;363():110011. doi: S0009-2797(22)00216-2.
Alharbi Khalid Saad, Almalki Waleed Hassan, Alzarea Sami I, Kazmi Imran, Al-Abbasi Fahad A, Afzal Obaid, Alfawaz Altamimi Abdulmalik Saleh, Singh Sachin Kumar, Dua Kamal, Gupta Gaurav,
Abstract
Cardiomyocyte regeneration following cardiac damage is challenging to study because of the inflammatory process, the multiplication of cells in the stroma, and the creation of scar tissue. In addition to the initial damage, the subsequent decrease in cardiac myocytes adds to heart failure. Piezo1 is remarkably understudied in the heart, which may be related to its recent discovery. Despite this, Piezo1 is expressed in a variety of cardiovascular cell populations, notably epithelial cells (EC), cardiac fibroblasts (CF), and cardiac myocytes (CM), in both animal and human samples, with fibroblasts expressing more than myocytes. Researchers have recently shown that disrupting Piezo1 signaling causes defects in zebrafish developing the outflow tract (OFT) and aortic valves. Platelet plasma membranes may provide lipid substrates, such as phosphatidylinositol bisphosphate, that aid in activating the piezo 1 ion channel in the cardiovascular system. In addition, CXC chemokine ligand 8/CXC chemokine receptor 1/2 (CXCL8-CXCR1/2) signaling was identified to establish the proliferation of coronary endothelial cells during cardiac regeneration. Notably, all these pathways are calcium-dependent, and cell proliferation and angiogenesis were necessary to recover myocardial cells. This review will examine the most current findings to understand further how platelet-rich plasma (PRP) and the piezo 1 channel might aid in cardiomyocyte regeneration.
Copyright © 2022 Elsevier B.V. All rights reserved.
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A mouse model for Li-Fraumeni-Like Syndrome with cardiac angiosarcomas associated to POT1 mutations.
PLoS Genet2022 Jun;18(6):e1010260. doi: 10.1371/journal.pgen.1010260.
Martínez Paula, Sánchez-Vázquez Raúl, Ferrara-Romeo Iole, Serrano Rosa, Flores Juana M, Blasco Maria A,
Abstract
The shelterin protein POT1 has been found mutated in many different familial and sporadic cancers, however, no mouse models to understand the pathobiology of these mutations have been developed so far. To address the molecular mechanisms underlying the tumorigenic effects of POT1 mutant proteins in humans, we have generated a mouse model for the human POT1R117C mutation found in Li-Fraumeni-Like families with cases of cardiac angiosarcoma by introducing this mutation in the Pot1a endogenous locus, knock-in for Pot1aR117C. We find here that both mouse embryonic fibroblasts (MEFs) and tissues from Pot1a+/ki mice show longer telomeres than wild-type controls. Longer telomeres in Pot1a+/ki MEFs are dependent on telomerase activity as they are not found in double mutant Pot1a+/ki Tert-/- telomerase-deficient MEFs. By using complementation assays we further show that POT1a pR117C exerts dominant-negative effects at telomeres. As in human Li-Fraumeni patients, heterozygous Pot1a+/ki mice spontaneously develop a high incidence of angiosarcomas, including cardiac angiosarcomas, and this is associated to the presence of abnormally long telomeres in endothelial cells as well as in the tumors. The Pot1a+/R117C mouse model constitutes a useful tool to understand human cancers initiated by POT1 mutations.
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Lipocalin-2: a novel link between the injured kidney and the bone.
Curr Opin Nephrol Hypertens2022 Jul;31(4):312-319. doi: 10.1097/MNH.0000000000000804.
Courbon Guillaume, David Valentin,
Abstract
PURPOSE OF REVIEW:
Fibroblast growth factor 23 (FGF23) excess is associated with left ventricular hypertrophy (LVH) and early mortality in patients with chronic kidney disease (CKD) and in animal models. Elevated Lipocalin-2 (LCN2), produced by the injured kidneys, contributes to CKD progression and might aggravate cardiovascular outcomes. The current review aims to highlight the role of LCN2 in CKD, particularly its interactions with FGF23.
RECENT FINDINGS:
Inflammation, disordered iron homeostasis and altered metabolic activity are common complications of CKD, and are associated with elevated levels of kidney-produced LCN2 and bone-secreted FGF23. A recent study shows that elevated LCN2 increases FGF23 production, and contributes to cardiac injury in patients and animals with CKD, whereas LCN2 reduction in mice with CKD reduces FGF23, improves cardiovascular outcomes and prolongs lifespan.
SUMMARY:
In this manuscript, we discuss the potential pathophysiological functions of LCN2 as a major kidney-bone crosstalk molecule, linking the progressive decline in kidney function to excessive bone FGF23 production. We also review associations of LCN2 with kidney, cardiovascular and bone and mineral alterations. We conclude that the presented data support the design of novel therapeutic approaches to improve outcomes in CKD.
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