Abstract 14223: Identifying Pro-fibrotic Long Non-coding RNAs Ii Fibroblasts From the Failing and Non-failing Human Sinoatrial Node

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Anuradha Kalyanasundaram ◽  
Ning LI ◽  
Brian Hansen ◽  
Miranda Gardner ◽  
Katelynn M Helfrich ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Sinoatrial Node ◽  
Transforming Growth Factor ◽  
Expression Patterns ◽  
Transforming Growth Factor Β1 ◽  
Right Atrial ◽  
Protein Coding ◽  
Molecular Approaches ◽  
Non Coding Rnas ◽  
Whole Transcriptome

Introduction: Dense fibrous connective tissue is inherently found in the human sinoatrial node (hSAN), which further increases in heart failure (HF) leading to sinoatrial node dysfunction (SND). While several factors contribute to cardiac fibrosis, it is unknown if long non-coding RNAs (lncRNA), a novel class of RNA known to affect cardiac fibrosis, are involved in increasing fibrotic content in hSAN in non-failing (nHF) vs HF hearts. Objective: To identify unique lncRNA profiles and pro-fibrotic lncRNAs in isolated SAN and right atrial (RA) fibroblasts (FBs), in HF vs nHF human hearts. Methods: FBs isolated from pure SAN and RA tissues, from HF (n=6; 35-68yo) and nHF (n=4; 26-64yo) cardioplegically arrested human hearts, were cultured with/without transforming growth factor β1 (TGFβ1; 5ng; 48hrs) to activate myofibroblast (myoFB) transition. Frozen FBs and myoFBs were subjected to high throughput Next Generation RNA Sequencing analyses of the whole transcriptome. Results: Averages of total counts across all samples revealed that majority of the genes detected were protein coding 14415(63%), 5876 (26%) lncRNA, 1254 (5%) miscellaneous RNA, 677(3%) miRNA and 577 (3%) other types of RNA (Figure A). Preliminary analyses show that coding mRNA and non-coding lncRNA are differentially expressed in nHF hSAN and RA fibroblasts and TGFβ1 treated myoFBs. Furthermore, these expression patterns were also different in FBs and myoFBs isolated from failing hearts. Conclusions: Our findings show for the first time that lncRNA expression in cultured hSAN Fbs and myoFBs are unique and differentially altered in HF. Ongoing analyses of sequenced transcriptome will identify FB and myoFB lncRNAs associated with intrinsic higher levels of hSAN fibrotic content as well as in HF. We will also determine if they can modify pro-fibrotic activity in HF SAN FBs and myoFBs, which may be beneficial to develop novel molecular approaches to decrease HF-associated SAN fibrosis and associated SND.

Aucubin Protects against TGFβ1-Induced Cardiac Fibroblasts Activation by Mediating the AMPKα/mTOR Signaling Pathway

Planta Medica ◽  
2017 ◽  
Vol 84 (02) ◽  
pp. 91-99 ◽  
Author(s):  
Yang Xiao ◽  
Wei Chang ◽  
Qing-Qing Wu ◽  
Xiao-Han Jiang ◽  
Ming-Xia Duan ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Smooth Muscle Actin ◽  
Mammalian Target Of Rapamycin ◽  
Transforming Growth Factor Β1 ◽  
Neonatal Rat ◽  
Cell Counting ◽  
Compound C ◽  
Underlying Mechanisms

AbstractFibrosis is a key feature of various cardiovascular diseases and compromises cardiac systolic and diastolic performance. The lack of effective anti-fibrosis drugs is a major contributor to the increasing prevalence of heart failure. The present study was performed to investigate whether the iridoid aucubin alleviates cardiac fibroblast activation and its underlying mechanisms. Neonatal rat cardiac fibroblasts were incubated with aucubin (1, 10, 20, 50 µM) followed by transforming growth factor β1 (TGFβ1, 10 ng/mL) stimulation for 24 h. Fibrosis proliferation was measured by cell counting kit-8 assay. The differentiation of fibroblasts into myofibroblasts was determined by measuring the expression of α-smooth muscle actin. Then, the expressions levels of cardiac fibrosis-related proteins in myofibroblasts were analyzed by western blot and real-time PCR to confirm the anti-fibrosis effect of aucubin. As a result, aucubin suppressed TGFβ1-induced proliferation in fibroblasts and inhibited the TGFβ1-induced activation of fibroblasts to myofibroblasts. In addition, aucubin further attenuated fibrosis-related protein expression in myofibroblasts. Furthermore, this protective effect was related to increased adenosine 5′-monophosphate-activated protein kinase (AMPK) phosphorylation and decreased mammalian target of rapamycin (mTOR) phosphorylation, which was confirmed by an mTOR inhibitor (rapamycin), an AMPK agonist (AICAR) and an AMPKα inhibitor compound C. Collectively, our findings suggest that aucubin protects against TGFβ1-induced fibroblast proliferation, activation and function by regulating the AMPKα/mTOR signal axis.

scholarly journals A Review of the Molecular Mechanisms Underlying Cardiac Fibrosis and Atrial Fibrillation

2021 ◽  
Vol 10 (19) ◽  
pp. 4430
Author(s):  
Grażyna Sygitowicz ◽  
Agata Maciejak-Jastrzębska ◽  
Dariusz Sitkiewicz
Keyword(s):  
Atrial Fibrillation ◽  
Molecular Mechanisms ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Signalling Pathways ◽  
Ang Ii ◽  
Atrial Fibrosis ◽  
Genes Encoding ◽  
Tgf Β1

The cellular and molecular mechanism involved in the pathogenesis of atrial fibrosis are highly complex. We have reviewed the literature that covers the effectors, signal transduction and physiopathogenesis concerning extracellular matrix (ECM) dysregulation and atrial fibrosis in atrial fibrillation (AF). At the molecular level: angiotensin II, transforming growth factor-β1, inflammation, and oxidative stress are particularly important for ECM dysregulation and atrial fibrotic remodelling in AF. We conclude that the Ang-II-MAPK and TGF-β1-Smad signalling pathways play a major, central role in regulating atrial fibrotic remodelling in AF. The above signalling pathways induce the expression of genes encoding profibrotic molecules (MMP, CTGF, TGF-β1). An important mechanism is also the generation of reactive oxygen species. This pathway induced by the interaction of Ang II with the AT2R receptor and the activation of NADPH oxidase. Additionally, the interplay between cardiac MMPs and their endogenous tissue inhibitors of MMPs, is thought to be critical in atrial ECM metabolism and fibrosis. We also review recent evidence about the role of changes in the miRNAs expression in AF pathophysiology and their potential as therapeutic targets. Furthermore, keeping the balance between miRNA molecules exerting anti-/profibrotic effects is of key importance for the control of atrial fibrosis in AF.

Ibuprofen Attenuates Cardiac Fibrosis in Streptozotocin-Induced Diabetic Rats

Cardiology ◽  
2015 ◽  
Vol 131 (2) ◽  
pp. 97-106 ◽  
Author(s):  
Weili Qiao ◽  
Cheng Wang ◽  
Bing Chen ◽  
Fan Zhang ◽  
Yaowu Liu ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Mammalian Target Of Rapamycin ◽  
Renin Angiotensin System ◽  
Transforming Growth Factor Β1 ◽  
Diabetic Rats ◽  
Diabetic Group ◽  
Significant Difference ◽  
Tgf Β1

Objective: To investigate the effects of ibuprofen on cardiac fibrosis in a rat model of type 1 diabetes. Methods: The diabetic model was established by injecting streptozotocin into the rats. Then, ibuprofen or pioglitazone was given by gavage for 8 weeks. The cardiac fibrosis was assessed, and the major components of the renin-angiotensin system, the transforming growth factor β1 (TGF-β1) and the mammalian target of rapamycin (mTOR), were evaluated by histopathological, immunohistochemical, Western blot analysis or ELISA assay. Results: Obvious cardiac fibrosis was detected in the diabetic group and was alleviated by ibuprofen treatment. Angiotensin-converting enzyme (ACE), angiotensin (Ang) II and AngII type 1 receptor (AT1-R) levels were higher, and ACE2, Ang(1-7) and Mas receptor (Mas-R) were lower in the diabetic group. The ratio of ACE to ACE2 was raised in the diabetic group. All these changes were ameliorated by ibuprofen. TGF-β1 and mTOR were raised in the hearts of the diabetic group and were attenuated by ibuprofen treatment. There was no significant difference between the ibuprofen and the pioglitazone groups. Conclusion: Ibuprofen could ameliorate the cardiac fibrosis in diabetic rats by reduction of the ACE/AngII/AT1-R axis and enhancement of the ACE2/Ang(1-7)/Mas-R axis, leading to a decrease in TGF-β1 and mTOR.

scholarly journals Emerging Roles of Estrogen-Regulated Enhancer and Long Non-Coding RNAs

2020 ◽  
Vol 21 (10) ◽  
pp. 3711
Author(s):  
Melina J. Sedano ◽  
Alana L. Harrison ◽  
Mina Zilaie ◽  
Chandrima Das ◽  
Ramesh Choudhari ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Expression Patterns ◽  
Biological Significance ◽  
Rna Seq ◽  
Biological Functions ◽  
Protein Coding ◽  
Rna Molecules ◽  
Non Coding Rna ◽  
Genome Wide ◽  
Non Coding Rnas

Genome-wide RNA sequencing has shown that only a small fraction of the human genome is transcribed into protein-coding mRNAs. While once thought to be “junk” DNA, recent findings indicate that the rest of the genome encodes many types of non-coding RNA molecules with a myriad of functions still being determined. Among the non-coding RNAs, long non-coding RNAs (lncRNA) and enhancer RNAs (eRNA) are found to be most copious. While their exact biological functions and mechanisms of action are currently unknown, technologies such as next-generation RNA sequencing (RNA-seq) and global nuclear run-on sequencing (GRO-seq) have begun deciphering their expression patterns and biological significance. In addition to their identification, it has been shown that the expression of long non-coding RNAs and enhancer RNAs can vary due to spatial, temporal, developmental, or hormonal variations. In this review, we explore newly reported information on estrogen-regulated eRNAs and lncRNAs and their associated biological functions to help outline their markedly prominent roles in estrogen-dependent signaling.

scholarly journals Recruitment of macrophages from the spleen contributes to myocardial fibrosis and hypertension induced by angiotensin II

2017 ◽  
Vol 18 (2) ◽  
pp. 147032031770665 ◽  
Author(s):  
Ning-Ping Wang ◽  
James Erskine ◽  
Wei-Wei Zhang ◽  
Rong-Hua Zheng ◽  
Li-Hui Zhang ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
At1 Receptor ◽  
Sprague Dawley ◽  
Monocyte Chemoattractant Protein 1 ◽  
Sprague Dawley Rats ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Introduction: The purpose of this study was to determine whether macrophages migrated from the spleen are associated with angiotensin II-induced cardiac fibrosis and hypertension. Methods: Sprague-Dawley rats were subjected to angiotensin II infusion in vehicle (500 ng/kg/min) for up to four weeks. In splenectomy, the spleen was removed before angiotensin II infusion. In the angiotensin II AT1 receptor blockade, telmisartan was administered by gastric gavage (10 mg/kg/day) during angiotensin II infusion. The heart and aorta were isolated for Western blot analysis and immunohistochemistry. Results: Angiotensin II infusion caused a significant reduction in the number of monocytes in the spleen through the AT1 receptor-activated monocyte chemoattractant protein-1. Comparison of angiotensin II infusion, splenectomy and telmisartan comparatively reduced the recruitment of macrophages into the heart. Associated with this change, transforming growth factor β1 expression and myofibroblast proliferation were inhibited, and Smad2/3 and collagen I/III were downregulated. Furthermore, interstitial/perivascular fibrosis was attenuated. These modifications occurred in coincidence with reduced blood pressure. At week 4, invasion of macrophages and myofibroblasts in the thoracic aorta was attenuated and expression of endothelial nitric oxide synthase was upregulated, along with a reduction in aortic fibrosis. Conclusions: These results suggest that macrophages when recruited into the heart and aorta from the spleen potentially contribute to angiotensin II-induced cardiac fibrosis and hypertension.

scholarly journals Characterisation and functional predictions of canine long non-coding RNAs

2018 ◽  
Author(s):  
Céline Le Béguec ◽  
Valentin Wucher ◽  
Lætitia Lagoutte ◽  
Edouard Cadieu ◽  
Nadine Botherel ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Expression Patterns ◽  
Regulatory Elements ◽  
Domestic Dog ◽  
Tissue Type ◽  
Protein Coding ◽  
Functional Roles ◽  
Integrative Study ◽  
Non Coding Rnas ◽  
Biological Functionality

AbstractLong non-coding RNAs (lncRNAs) are a family of heterogeneous RNAs that play major roles in multiple biological processes. We recently identified an extended repertoire of more than 10,000 lncRNAs of the domestic dog however, predicting their biological functionality remains challenging. In this study, we have characterised the expression profiles of 10,444 canine lncRNAs in 26 distinct tissue types, representing various anatomical systems. We showed that lncRNA expressions are mainly clustered by tissue type and we highlighted that 44% of canine lncRNAs are expressed in a tissue-specific manner. We further demonstrated that tissue-specificity correlates with specific families of canine transposable elements. In addition, we identified more than 900 conserved dog-human lncRNAs for which we show their overall reproducible expression patterns between dog and humans through comparative transcriptomics. Finally, co-expression analyses of lncRNA and neighbouring protein-coding genes identified more than 3,400 canine lncRNAs, suggesting that functional roles of these lncRNAs act as regulatory elements. Altogether, this genomic and transcriptomic integrative study of lncRNAs constitutes a major resource to investigate genotype to phenotype relationships and biomedical research in the dog species.

Abstract 230: Cartilage Intermediate Layer Protein-1 Attenuates Pressure Overload-induced Cardiac Fibrosis by Targeting Transforming Growth Factor-β1

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Li Li ◽  
Cheng-Lin Zhang ◽  
Dan Wu ◽  
Li-Ling Wu
Keyword(s):  
Growth Factor ◽  
Intermediate Layer ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Pressure Overload ◽  
Transforming Growth Factor Β1 ◽  
Tgf Β1

Background: Cartilage intermediate layer protein-1 (CILP-1), a monomeric extracellular matrix glycoprotein expressed mainly in the middle zones of articular cartilage, interacts directly with transforming growth factor-β1 (TGF-β1). Recent studies showed that CILP-1 was upregulated in the heart tissue following cardiac ischemia reperfusion injury. However, the role of CILP-1 in pathological cardiac remodeling is poorly defined. Aims: To explore the effect of CILP-1 on myocardial interstitial fibrosis and reveal the possible molecular mechanism. Methods and Results: We found that CILP-1 was mainly expressed in mouse cardiac fibroblasts (CFs) by using western blot analysis and immunofluorescence. Myocardial expression of CILP-1 was upregulated in mice subjected to transverse aortic constriction (TAC) for 2, 4, and 8 weeks. AAV-9-mediated delivery of CILP-1 into mice increased the binding of CILP-1 with TGF-β1, attenuated interstitial fibrosis, and improved cardiac function. In cultured adult mouse CFs, CILP-1 overexpression inhibited myofibroblast differentiation and expression of profibrotic molecules induced by TGF-β1. Furthermore, CILP-1 attenuated TGF-β1-induced Smad3 phosphorylation and nuclear translocation. Conclusions: CILP-1 alleviates pressure overload-induced cardiac fibrosis and dysfunction. CILP-1 exerts its anti-fibrotic effect through targeting TGF-β1 signaling. This study will offer a new therapeutic strategy for preventing and treating myocardial interstitial remodeling.

scholarly journals Role for high-glucose-induced protein O-GlcNAcylation in stimulating cardiac fibroblast collagen synthesis

2014 ◽  
Vol 306 (9) ◽  
pp. C794-C804 ◽  
Author(s):  
Hugo Aguilar ◽  
Eduardo Fricovsky ◽  
Sang Ihm ◽  
Magdalena Schimke ◽  
Lisandro Maya-Ramos ◽  
...  
Keyword(s):  
High Glucose ◽  
Collagen Synthesis ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Transforming Growth Factor Β1 ◽  
Protein Levels ◽  
Normal Glucose ◽  
Arginase Ii ◽  
Tgf Β1

Excess enzyme-mediated protein O-GlcNAcylation is known to occur with diabetes mellitus. A characteristic of diabetic cardiomyopathy is the development of myocardial fibrosis. The role that enhanced protein O-GlcNAcylation plays in modulating the phenotype of cardiac fibroblasts (CF) is unknown. To address this issue, rat CF were cultured in normal glucose (NG; 5 mM glucose) or high-glucose (HG; 25 mM) media for 48 h. Results demonstrate that CF cultured in HG have higher levels (∼50%) of overall protein O-GlcNAcylation vs. NG cells. Key regulators of collagen synthesis such as transforming-growth factor-β1 (TGF-β1), SMADs 2/3, and SMAD 7 protein levels, including those of arginase I and II, were altered, leading to increases in collagen levels. The nuclear transcription factor Sp1 and arginase II evidence excess O-GlcNAcylation in HG cells. Expression in CF of an adenovirus coding for the enzyme N-acetylglucosaminidase, which removes O-GlcNAc moieties from proteins, decreased Sp1 and arginase II O-GlcNAcylation and restored HG-induced perturbations in CF back to NG levels. These findings may have important pathophysiological implications for the development of diabetes-induced cardiac fibrosis.

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