264The long noncoding RNA H19 modulates cardiac remodeling after infarction

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
O K Choong ◽  
C Y Chen ◽  
J H Lin ◽  
P J Lin ◽  
J H Zhang ◽  
...  
Keyword(s):  
Cardiac Remodeling ◽  
Noncoding Rna ◽  
Cardiac Fibrosis ◽  
Cardiac Development ◽  
Cardiac Fibroblasts ◽  
Noncoding Rnas ◽  
Interacting Protein ◽  
Functional Studies ◽  
Rna Purification

Abstract Noncoding RNAs account for 80% of human transcripts, but functional studies on noncoding RNAs are relatively few and limited. Long noncoding RNAs (lncRNAs) are known to have an important role in cardiac development, and lately, high-throughput RNA sequencing has been extensively utilized to profile and explore the transcriptome landscape of lncRNAs in failing hearts. These studies have revealed that lncRNAs are mostly dysregulated in failing hearts and their expression signature can discriminate failing hearts of different etiologies. H19 is abundantly expressed in failing human hearts and its polymorphism was shown to possess a significant correlation with the risk of coronary artery diseases. In our study using murine hearts, we discovered that H19 was significantly up regulated in the heart after ischemic injury, with predominant expression in cardiac fibroblasts. This finding piqued our interest to further investigate the function of H19 in the heart. We demonstrated that ectopic overexpression of H19 using the AAV approach led to severe cardiac fibrosis in mouse hearts following myocardial infarction. In light of this finding, we generated H19 knockout mice to further investigate the functionality of H19 and we found that cardiac fibrosis was attenuated in these mice. Altogether, these findings suggested that H19 is a fibrosis regulator during cardiac remodeling process after infarction. Due to the multiple regulatory roles of lncRNAs, we then took advantage of chromatin isolation by RNA purification (ChIRP) to identify the H19-interacting protein, YB-1. Surprisingly, mice with YB-1 knockdown displayed severe cardiac fibrosis even without injury. Furthermore, we demonstrated that YB-1 is a transcriptional suppressor of collagen 1A1. Knockout of H19 in YB-1 knockdown partially suppressed Col1a1 expression, which suggests a negative regulatory role of H19 on YB-1 towards the expression of Col1a1. Taking into account all of these findings, we concluded that H19 mediates collagen expression in fibroblasts through the inhibition of YB-1 activity during cardiac remodeling.

Abstract MP259: The Role Of Sertad4 In Pathological Cardiac Remodeling

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Matthew Stratton ◽  
Ashley Francois ◽  
Oscar Bermeo-Blanco ◽  
Alessandro Canella ◽  
Lynn Marcho ◽  
...  
Keyword(s):  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Systolic Function ◽  
Myocardial Infarct ◽  
Proteasome Inhibition ◽  
Rna Seq ◽  
Expression Of Genes ◽  
M Phase ◽  
Tgf Β1

Over 6 million Americans suffer from heart failure (HF) while the 5-year mortality rate following first admission for HF is over 40%. Cardiac fibrosis is a clinical hallmark of HF, regardless of the initiating pathology and is thought to contribute to disease progression. Using an epigenomics discovery approach, we uncovered a nuclear protein, Sertad4, as a potential anti-fibrotic target. Our data indicate that Sertad4 is a positive regulator of fibroblast activation. Specifically, cultured cardiac fibroblast experiments demonstrate that Sertad4 targeting with shRNAs blocks fibroblast proliferation and causes cells to arrest in the G2/M phase of the cell cycle. Also, shRNA targeting of Sertad4 dramatically blocked activation of myofibroblast differentiation genes (αSMA/POSTN/COL1A1). Mechanistically, these effects appear to be mediated by Sertad4 regulation of SMAD2 protein stability in the presence of TGF-β1 stimulation as demonstrated by proteasome inhibition experiments. RNA-seq analysis indicate that Sertad4 also regulates the expression of genes involved in ubiquitination and proteasome degradation. Next, we sought to determine the effect of global Sertad4 knockout on post-myocardial infarct (MI) remodeling and cardiac function in mice. After 4 weeks of permanent LAD ligation, echocardiography was performed to measure systolic function. Relative to wild-type (WT) controls, the Sertad4 KO mice showed preserved systolic function as evident by improved ejection fraction (WT 14.4 +/- 3.6 vs. KO 33.9+/-5.9, p=0.035) and fractional shortening (WT 6.5 +/- 1.7 vs. KO 16.4 +/- 3.4, p=0.046). β-gal staining in the Sertad4/LacZ reporter mouse subjected to MI showed robust Sertad4/LacZ expression in the ischemic scar and boarder-zone with almost no expression in control hearts. This data supports the notion that Sertad4 has a key role in cardiac remodeling in response to ischemic injury.

Abstract 237: Sex-specific Regulation Of Collagen I And III Expression By 17β-estradiol In Rat Cardiac Fibroblasts: Role Of Estrogen Receptors

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Elke Dworatzek ◽  
Shokoufeh Mahmoodzadeh ◽  
Sandra Kunze ◽  
Vera Regitz-Zagrosek
Keyword(s):  
Sex Differences ◽  
Western Blot ◽  
Estrogen Receptors ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Collagen I ◽  
Female Rats ◽  
17Β Estradiol ◽  
Specific Regulation

Clinical and animal studies showed in female pressure-overloaded hearts less cardiac fibrosis and collagen I and III gene expression compared to males, suggesting an inhibitory effect of 17β-Estradiol (E2) on collagens. Therefore we investigated the role of E2 and estrogen receptors (ER) on collagen I and III expression in isolated rat cardiac fibroblasts from both sexes. Cardiac fibroblasts were isolated from adult male and female Wistar rats, and treated with E2 (10-8M), vehicle, ERα and ERβ-agonist (10-7M) and/or pre-treated with ICI 182,780 (10-5M) for 24h. Cellular localization of ER in cardiac fibroblasts with/without E2 was detected by immunofluorescence staining, and expression of both ER was determined by western blot. Expression of collagen I and III was determined by qRT-PCR and western blot. E2-treatment led to a nuclear translocation of ERα and ERβ in cardiac fibroblasts, suggesting the functional activity of ER as transcription factors. Furthermore in cardiac fibroblasts from female rats E2 led to a significant down-regulation of collagen I and III gene and protein expression. In contrast there was a significant increase of collagen I and III levels in fibroblasts isolated from male rat hearts by E2. E2-effect could be inhibited by ICI 182, 780 indicating the involvement of ER. In cardiac fibroblasts from female rats, ERα-agonist treatment led to a significant down-regulation of collagen I and III mRNA level, but ERβ-agonist had no effects. In contrast, ERβ-agonist treatment of cardiac fibroblasts from males increased collagen I and III mRNA, but no changes with ERα agonist-treatment were detected. ERα protein levels displayed no sex differences at basal level. After E2-treatment ERα protein was up-regulated in male cells, but decreased in cardiac fibroblasts from females. ERβ protein was higher in female cells compared to males, but the expression was not regulated by E2 in both sexes. Sex-specific regulation of collagen I and III expression by E2 in cardiac fibroblasts might be responsible for sex-differences in cardiac fibrosis. This might be due to sexually dimorphic ER expression and regulation. Understanding how E2 and ER mediate sex-differences in cardiac remodeling may help to design sex-specific pharmacological interventions.

Abstract 445: A Pro-Fibrotic Role of Interleukin-4 in Cardiac Remodeling and Dysfunction

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Hongmei Peng ◽  
Oscar Carretero ◽  
Xiao-Ping Yang ◽  
Pablo Nakagawa ◽  
Jiang Xu ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Interleukin 4 ◽  
Ang Ii ◽  
Collagen Production ◽  
And Function ◽  
First Time ◽  
Mini Pump

Elevated interleukin-4 (IL-4) levels are positively related to cardiac fibrosis in heart failure and hypertension. Using Balb/c exhibiting high circulating IL-4, Balb/c- Il4 tm2Nnt (IL-4 knockout with Balb/c background, IL-4 -/- ) and C57BL/6 mice, as well as cultured cardiac fibroblasts (CFs), we hypothesized that 1) high levels of IL-4 result in cardiac fibrosis, making the heart susceptible to angiotensin II (Ang II)-induced damage, and 2) IL-4 potently stimulates collagen production by CFs. Each strain (9- to 12-week old male) received vehicle or Ang II (1.4 mg/kg/day, s.c. via osmotic mini-pump) for 8 weeks. Cardiac fibrosis and function were determined by histology and echocardiography, respectively. Compared to C57BL/6, Balb/c mice had doubled interstitial collagen in the heart, enlarged left ventricle and decreased cardiac function along with elevated cardiac IL-4 protein (1.00±0.08 in C57BL/6 vs 2.61±0.46 in Balb/c, p <0.05); all those changes were significantly attenuated in IL-4 -/- (Table 1). Ang II further deteriorated cardiac fibrosis and dysfunction in Balb/c; these detrimental effects were attenuated in IL-4 -/- , although the three strains had a similar level of hypertension. In vitro study revealed that IL-4Rα was constitutively expressed in CFs (Western blot), and IL-4 potently stimulated collagen production by CFs (hydroxproline assay, from 18.89±0.85 to 38.81±3.61 μg/mg at 10 ng/ml, p <0.01). Our study demonstrates for the first time that IL-4, as a potent pro-fibrotic cytokine in the heart, contributes to cardiac fibrotic remodeling and dysfunction. Thus IL-4 may be a potential therapeutic target for cardiac fibrosis and dysfunction.

scholarly journals A Review of CXCL1 in Cardiac Fibrosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Cheng-Long Wu ◽  
Ran Yin ◽  
Su-Nan Wang ◽  
Ru Ying
Keyword(s):  
Cardiovascular Diseases ◽  
Serum Level ◽  
Inflammatory Reaction ◽  
Cardiac Remodeling ◽  
Recent Progress ◽  
Cardiac Fibrosis ◽  
Elevated Serum ◽  
Inflammatory Factor ◽  
Growing Body

Chemokine C-X-C motif ligand-1 (CXCL1), principally expressed in neutrophils, macrophages and epithelial cells, is a valid pro-inflammatory factor which performs an important role in mediating the infiltration of neutrophils and monocytes/macrophages. Elevated serum level of CXCL1 is considered a pro-inflammatory reaction by the organism. CXCL1 is also related to diverse organs fibrosis according to relevant studies. A growing body of evidence suggests that CXCL1 promotes the process of cardiac remodeling and fibrosis. Here, we review structure and physiological functions of CXCL1 and recent progress on the effects and mechanisms of CXCL1 in cardiac fibrosis. In addition, we explore the role of CXCL1 in the fibrosis of other organs. Besides, we probe the possibility that CXCL1 can be a therapeutic target for the treatment of cardiac fibrosis in cardiovascular diseases.

scholarly journals EPRS Regulates Proline-rich Pro-fibrotic Protein Synthesis during Cardiac Fibrosis

2019 ◽  
Author(s):  
Jiangbin Wu ◽  
Kadiam C Venkata Subbaiah ◽  
Li Huitong Xie ◽  
Feng Jiang ◽  
Deanne Mickelsen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Remodeling ◽  
Translational Control ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Mrna Translation ◽  
Trna Synthetase ◽  
Mouse Heart ◽  
List Type ◽  
Human And Mouse

AbstractRationaleIncreased protein synthesis of pro-fibrotic genes is a common feature of cardiac fibrosis, a major manifestation of heart failure. Despite this important observation, critical factors and molecular mechanisms for translational control of pro-fibrotic genes during cardiac fibrosis remain unclear.ObjectiveThis study aimed to test the hypothesis that cardiac stress-induced expression of a bifunctional aminoacyl-tRNA synthetase (ARS), glutamyl-prolyl-tRNA synthetase (EPRS), is preferentially required for the translation of proline codon-rich (PRR) pro-fibrotic mRNAs in cardiac fibroblasts during cardiac fibrosis.Methods and ResultsBy analyses of multiple available unbiased large-scale screening datasets of human and mouse heart failure, we have discovered that EPRS acts as an integrated node among all the ARSs in various cardiac pathogenic processes. We confirmed that EPRS was induced at both mRNA and protein level (∼1.5-2.5 fold increase) in failing hearts compared with non-failing hearts using our cohort of human and mouse heart samples. Genetic knockout of one allele of Eprs globally (Eprs+/-) using CRISPR-Cas9 technology or in a myofibroblast-specific manner (Eprsflox/+; PostnMCM/+) strongly reduces cardiac fibrosis (∼50% reduction) in isoproterenol- and transverse aortic constriction-induced heart failure mouse models. Inhibition of EPRS by a prolyl-tRNA synthetase (PRS)-specific inhibitor, halofuginone (Halo), significantly decreased the translation efficiency of proline-rich collagens in cardiac fibroblasts. Furthermore, using transcriptome-wide RNA-Seq and polysome profiling-Seq in Halo-treated fibroblasts, we identified multiple novel Pro-rich genes in addition to collagens, such as Ltbp2 and Sulf1, which are translationally regulated by EPRS. As a major EPRS downstream effector, SULF1 is highly enriched in human and mouse myofibroblast. siRNA-mediated knockdown of SULF1 attenuates cardiac myofibroblast activation and collagen deposition.ConclusionsOur results indicate that EPRS preferentially controls the translational activation of proline codon-rich pro-fibrotic genes in cardiac fibroblasts and augments pathological cardiac remodeling.Novelty and SignificanceWhat is known?TGF-β and IL-11 increase synthesis of pro-fibrotic proteins during cardiac fibrosis.Many pro-fibrotic genes contain Pro genetic codon rich motifs such as collagens.EPRS is an essential house-keeping enzyme required for ligating Pro to tRNAPro for the synthesis of Pro-containing proteins.What New Information Does This Article Contribute?This study is a pioneering investigation of translational control mechanisms of pro-fibrotic gene expression in cardiac fibrosis.EPRS mRNA and protein expression are induced in failing human hearts and mouse hearts undergoing pathological cardiac remodeling.The first demonstration of the in vivo function of EPRS in cardiac remodeling. Heterozygous Eprs global knockout and myofibroblast-specific tamoxifen-inducible Eprs conditional knockout mice show reduced pathological cardiac fibrosis under stress, suggesting that the reduction of EPRS is cardioprotective.Identification of novel preferential translational target genes of EPRS. We found that EPRS regulates translation of Pro-rich (PRR) transcripts, which comprise most of the ECM and secretory signaling molecules. Among those targets, we identified multiple novel PRR genes such as LTBP2 and SULF1.SULF1 is validated as a myofibroblast marker protein in human and mouse heart failure and a potential anti-fibrosis target gene.In cardiac fibroblasts, the synthesis of pro-fibrotic proteins is upregulated by cardiac stressors to activate extracellular matrix deposition and impair cardiac function. In this study, we have discovered an EPRS-PRR gene axis that influences translational homeostasis of pro-fibrotic proteins and promotes pathological cardiac remodeling and fibrosis. EPRS is identified as a common node downstream of multiple cardiac stressors and a novel regulatory factor that facilitates pro-fibrotic mRNA translation in cardiac fibrosis. Global and myofibroblast-specific genetic ablation of EPRS can effectively reduce cardiac fibrosis. This study reveals a novel translational control mechanism that modulates cardiac fibrosis and heart function. Mild inhibition of PRR mRNA translation could be a general therapeutic strategy for the treatment of heart disease. These findings provide novel insights into the translational control mechanisms of cardiac fibrosis and will promote the development of novel therapeutics by inhibiting pro-fibrotic translation factors or their downstream effectors.

scholarly journals miR-21 is upregulated, promoting fibrosis and blocking G2/M in irradiated rat cardiac fibroblasts

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10502
Author(s):  
Huan Guo ◽  
Xinke Zhao ◽  
Haixiang Su ◽  
Chengxu Ma ◽  
Kai Liu ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Target Genes ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Differentially Expressed Gene ◽  
Stem Loop ◽  
Cardiac Morbidity ◽  
Increased Risk ◽  
And Function

Background Radiation exposure of the thorax is associated with a greatly increased risk of cardiac morbidity and mortality even after several decades of advancement in the field. Although many studies have demonstrated the damaging influence of ionizing radiation on cardiac fibroblast (CF) structure and function, myocardial fibrosis, the molecular mechanism behind this damage is not well understood. miR-21, a small microRNA, promotes the activation of CFs, leading to cardiac fibrosis. miR-21 is overexpressed after irradiation; however, the relationship between increased miR-21 and myocardial fibrosis after irradiation is unclear. This study was conducted to investigate gene expression after radiation-induced CF damage and the role of miR-21 in this process in rats. Methods We sequenced irradiated rat CFs and performed weighted correlation network analysis (WGCNA) combined with differentially expressed gene (DEG) analysis to observe the effect on the expression profile of CF genes after radiation. Results DEG analysis showed that the degree of gene changes increased with the radiation dose. WGCNA revealed three module eigengenes (MEs) associated with 8.5-Gy-radiation—the Yellow, Brown, Blue modules. The three module eigengenes were related to apoptosis, G2/M phase, and cell death and S phase, respectively. By blocking with the cardiac fibrosis miRNA miR-21, we found that miR-21 was associated with G2/M blockade in the cell cycle and was mainly involved in regulating extracellular matrix-related genes, including Grem1, Clu, Gdf15, Ccl7, and Cxcl1. Stem-loop quantitative real-time PCR was performed to verify the expression of these genes. Five genes showed higher expression after 8.5 Gy-radiation in CFs. The target genes of miR-21 predicted online were Gdf15 and Rsad2, which showed much higher expression after treatment with antagomir-miR-21 in 8.5-Gy-irradiated CFs. Thus, miR-21 may play the role of fibrosis and G2/M blockade in regulating Grem1, Clu, Gdf15, Ccl7, Cxcl1, and Rsad2 post-irradiation.

scholarly journals Long Noncoding RNA and Epithelial Mesenchymal Transition in Cancer

2019 ◽  
Vol 20 (8) ◽  
pp. 1924 ◽  
Author(s):  
Gugnoni ◽  
Ciarrocchi
Keyword(s):  
Cancer Biology ◽  
Noncoding Rna ◽  
Epithelial Mesenchymal Transition ◽  
Protein Localization ◽  
Noncoding Rnas ◽  
Therapeutic Targets ◽  
Mesenchymal Transition ◽  
Multistep Process ◽  
Genomic Studies

Epithelial–mesenchymal transition (EMT) is a multistep process that allows epithelial cells to acquire mesenchymal properties. Fundamental in the early stages of embryonic development, this process is aberrantly activated in aggressive cancerous cells to gain motility and invasion capacity, thus promoting metastatic phenotypes. For this reason, EMT is a central topic in cancer research and its regulation by a plethora of mechanisms has been reported. Recently, genomic sequencing and functional genomic studies deepened our knowledge on the fundamental regulatory role of noncoding DNA. A large part of the genome is transcribed in an impressive number of noncoding RNAs. Among these, long noncoding RNAs (lncRNAs) have been reported to control several biological processes affecting gene expression at multiple levels from transcription to protein localization and stability. Up to now, more than 8000 lncRNAs were discovered as selectively expressed in cancer cells. Their elevated number and high expression specificity candidate these molecules as a valuable source of biomarkers and potential therapeutic targets. Rising evidence currently highlights a relevant function of lncRNAs on EMT regulation defining a new layer of involvement of these molecules in cancer biology. In this review we aim to summarize the findings on the role of lncRNAs on EMT regulation and to discuss their prospective potential value as biomarkers and therapeutic targets in cancer.

scholarly journals MicroRNA-101a Inhibits Cardiac Fibrosis Induced by Hypoxia via Targeting TGFβRI on Cardiac Fibroblasts

2015 ◽  
Vol 35 (1) ◽  
pp. 213-226 ◽  
Author(s):  
Xin Zhao ◽  
Kejing Wang ◽  
Yuhua Liao ◽  
Qiutang Zeng ◽  
Yushu Li ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Transforming Growth Factor Beta ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Luciferase Reporter ◽  
Migration Ability

Background/Aims: Hypoxia is a basic pathological challenge that is associated with numerous cardiovascular disorders including aberrant cardiac remodeling. Transforming growth factor beta (TGF-β) signaling pathway plays a pivotal role in mediating cardiac fibroblast (CF) function and cardiac fibrosis. Recent data suggested that microRNA-101a (miR-101a) exerted anti-fibrotic effects in post-infarct cardiac remodeling and improved cardiac function. This study aimed to investigate the potential relationship between hypoxia, miR-101a and TGF-β signaling pathway in CFs. Methods and Results: Two weeks following coronary artery occlusion in rats, the expression levels of both TGFβ1 and TGFβRI were increased, but the expression of miR-101a was decreased at the site of the infarct and along its border. Cultured rat neonatal CFs treated with hypoxia were characterized by the up-regulation of TGFβ1 and TGFβRI and the down-regulation of miR-101a. Delivery of miR-101a mimics significantly suppressed the expression of TGFβRI and p-Smad 3, CF differentiation and collagen content of CFs. These anti-fibrotic effects were abrogated by co-transfection with AMO-miR-101a, an antisense inhibitor of miR-101a. The repression of TGFβRI, a target of miR-101a, was validated by luciferase reporter assays targeting the 3'UTR of TGFβRI. Additionally, we found that overexpression of miR-101a reversed the improved migration ability of CFs and further reduced CF proliferation caused by hypoxia. Conclusion: Our study illustrates that miR-101a exerts anti-fibrotic effects by targeting TGFβRI, suggesting that miR-101a plays a multi-faceted role in modulating TGF-β signaling pathway and cardiac fibrosis.

scholarly journals Downregulation of S100A4 Alleviates Cardiac Fibrosis via Wnt/β -Catenin Pathway in Mice

2018 ◽  
Vol 46 (6) ◽  
pp. 2551-2560 ◽  
Author(s):  
LiJun Qian ◽  
Jian Hong ◽  
YanMei Zhang ◽  
MengLin Zhu ◽  
XinChun Wang ◽  
...  
Keyword(s):  
Calcium Binding ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Group A ◽  
Ischemic Diseases ◽  
Fibrotic Diseases ◽  
Signaling Activation

Background/Aims: Cardiac fibrosis is a pathological change leading to cardiac remodeling during the progression of myocardial ischemic diseases, and its therapeutic strategy remains to be explored. S100A4, a calcium-binding protein, participates in fibrotic diseases with an unclear mechanism. This study aimed to investigate the role of S100A4 in cardiac fibrosis. Methods: Cardiac fibroblasts from neonatal C57BL/6 mouse hearts were isolated and cultured. Myocardial infarction was induced by ligating the left anterior descending coronary artery (LAD). The ligation was not performed in the sham group. A volume of 5×105pfu/g adenovirus or 5 µM/g ICG-001 was intramyocardially injected into five parts bordering the infarction zone or normal region. We used Western blotting, quantitative RT-PCR, immunofluorescence, immunohistochemistry and Masson’s trichrome staining to explore the function of S100A4. Results: We found significant increases of S100A4 level and cardiac fibrosis markers, and β-catenin signaling activation in vitro and in vivo. In addition, knockdown of S100A4 significantly reduced cardiac fibrosis and β-catenin levels. Moreover, the expression of S100A4 decreased after ICG-001 inhibited β-catenin signal pathway. Conclusion: Downregulation of S100A4 alleviates cardiac fibrosis via Wnt/β -catenin pathway in mice. S100A4 may be a therapeutic target of cardiac fibrosis.

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