Differential Behaviors of Atrial Versus Ventricular Fibroblasts A Potential Role for Platelet-Derived Growth Factor in Atrial-Ventricular Remodeling Differences
TL;DR: Atrial fibroblasts behave differently than ventricular fibro Blasts over a range of in vitro and in vivo paradigms, with atrial Fibroblast showing enhanced reactivity that may explain greater atrial fibrotic responses.
Abstract: Background— In various heart disease paradigms, atria show stronger fibrotic responses than ventricles. The possibility that atrial and ventricular fibroblasts respond differentially to pathological stimuli has not been examined. Methods and Results— We compared various morphological, secretory, and proliferative response indexes of canine atrial versus ventricular fibroblasts. Cultured atrial fibroblasts showed faster cell surface area increases, distinct morphology at confluence, and greater α-smooth muscle actin expression than ventricular fibroblasts. Atrial fibroblast proliferation ([3H]thymidine incorporation) responses were consistently greater for a range of growth factors, including fetal bovine serum, platelet-derived growth factor (PDGF), basic fibroblast growth factor, angiotensin II, endothelin-1, and transforming growth factor-β1. Normal atrial tissue showed larger myofibroblast density compared with ventricular tissue, and the difference was exaggerated by congestive heart failure. Congesti...
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TL;DR: Strong evidence is presented demonstrating that, in addition to and distinct from the role of the RAAS, histone deacetylase (HDAC) overactivity causes atrial fibrosis, connexin-40 downregulation and atrial arrhythmia susceptibility in transgenic mice, and that pharmacologic inhibition of HDAC suppresses deleterious atrial remodeling.
8 citations
Cites background from "Differential Behaviors of Atrial Ve..."
...This fibrosis is the result of fibroblast proliferation and associated increases in extracellular matrix production, with atrial fibroblasts showing enhanced proliferative and synthetic responses compared to ventricular [4]....
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...In addition to HDAC mediated signaling, oxidant stress (via modulation of matrix metalloproteinase, MMP, activity), transforming growth factor-β (TGFβ), platelet-derived growth factor (PDGF) and inflammatory pathways are likely to promote atrial fibrosis [4,11,17]....
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Dissertation•
01 Jan 2015
TL;DR: This chapter discusses the epidemiology of Atrial Fibrillation, and the role of substrate in the development of atrial structural remodeling.
Abstract: ........................................................................................................................... XI Declaration .................................................................................................................. XIV Acknowledgements ..................................................................................................... XV Publications and Communications to Learned Societies ............................... 16 Prizes and Awards during Candidature .................................................................. 1 Chapter 1: Literature Review .................................................................................... 1 1.1 Epidemiology of Atrial Fibrillation ........................................................................ 1 1.2 Initiation of Atrial Fibrillation ................................................................................. 3 1.2.1 Multiple Wavelet Hypothesis ......................................................................................... 3 1.2.2 Role of Triggers .................................................................................................................... 4 1.3 Maintenance of AF: Role of substrate .................................................................... 6 1.4 Common clinical substrates ..................................................................................... 8 1.4.1 Age .............................................................................................................................................. 9 1.4.2 Congestive heart failure .................................................................................................... 9 1.4.3 Mitral valve disease .......................................................................................................... 10 1.4.4 Atrial septal defect ............................................................................................................ 11 1.4.5 Coronary artery disease ................................................................................................. 11 1.4.6 Hypertension ....................................................................................................................... 12 1.4.7 Diabetes ................................................................................................................................. 13 1.4.8 Obstructive sleep apnoea ............................................................................................... 13 1.5 Mechanism of atrial structural remodeling ..................................................... 15 1.5.1 Neurohormonal factors: ................................................................................................. 15 1.5.2 Tissue factors ...................................................................................................................... 16
8 citations
Cites background from "Differential Behaviors of Atrial Ve..."
...Notably, this was in conjunction with increased tissue levels of Angiotensin II levels.175 CTGF is a downstream mediator of Angiotensin II and TGFβ1....
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...PDGF receptor activation stimulates the mitogen-activated protein kinase, JAK/ STAT, and phospholipase C pathways, a final common pathway shared by Angiotensin II and TGFβ1.(186) The gene expression of PDGF and its receptors is stronger in the atrial than ventricular rat fibroblasts....
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...This could explain why atria are much more susceptible to fibrotic remodeling than ventricles.(186) PDGF receptor inhibition prevents the electromechanical remodelling of adult atrial myocytes and may serve as a novel potential therapeutic target of AF....
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TL;DR: CAV1 is critical for the MG53 regulation of TGF-β1 signaling pathway-induced atrial fibrosis in AF and provides a potential therapeutic target for fibrosis and AF.
Abstract: Atrial fibrosis plays a significant role in the development of atrial fibrillation (AF). Previously, we showed that mitsugumin 53 (MG53) regulates TGF-β1 signaling pathway-induced atrial fibrosis. Recent studies have shown that caveolin-1 (CAV1) is an important anti-fibrosis signaling mediator that inhibits the TGF-β1 signaling pathway. Here, we further study the mechanism underlying the related action of MG53 and CAV1. We demonstrate that CAV1 expression was decreased while MG53 expression was increased in atrial tissue from AF patients. In cultured atrial fibroblasts, MG53 depletion by siRNA caused CAV1 upregulation and TGF-β1/SMAD2 signaling pathway downregulation, while MG53 overexpression via adenovirus had the opposite effect. CAV1 inactivated the TGF-β1/SMAD2 signaling pathway. In addition, using an Ang II-induced fibrosis model, we show that MG53 regulates TGF-β1 signaling via CAV1. Therefore, CAV1 is critical for the MG53 regulation of TGF-β1 signaling pathway-induced atrial fibrosis in AF. These findings reveal the related underlying mechanism of action of MG53 and CAV1 and provide a potential therapeutic target for fibrosis and AF.
8 citations
TL;DR: In this paper, the authors explore the function of miR-29b-3p in regulating atrial remodeling by targeting PDGF-B signaling pathway and thereby also explore the potential mechanisms.
Abstract: Purpose Studies have found that microRNAs (miRNAs) are closely associated with atrial fibrillation, but their specific mechanism remains unclear. The purpose of this experiment is to explore the function of miR-29b-3p in regulating atrial remodeling by targeting PDGF-B signaling pathway and thereby also explore the potential mechanisms. Methods We randomly divided twenty-four rats into four groups. Caudal intravenous injections of angiotensin-II (Ang-II) were administered to establish atrial fibrosis models. Expressions of miR-29b-3p and PDGF-B were then tested via RT-PCR, western blot, and immunohistochemistry. Binding sites were then analyzed via the bioinformatics online software TargetScan and verified by Luciferase Reporter. We used Masson staining to detect the degree of atrial fibrosis, while immunofluorescence and western blot were used to detect the expressions of Collagen-I and a-SMA. We used immunohistochemistry and western blot to detect the expression of connexin 43 (Cx43). Results In comparison with the Ang-II group, miR-29b-3p was seen to lower the degree of atrial fibrosis, decrease the expression of fibrosis markers such as Collagen-I and a-SMA, and increase the protein expression of Cx43. MiR-29b-3p can lower the expression of PDGF-B, while the Luciferase Reporter showed that PDGF-B is the verified target gene of miR-29b-3p. Conclusions MiR-29b-3p was able to reduce atrial structural and electrical remodeling in the study's rat fibrosis model. This biological function may be expressed through the targeted regulation of the PDGF-B signaling pathway.
8 citations
TL;DR: The current knowledge on exercise-induced atrial fibrillation is reviewed through different perspectives, each focusing on the epidemiological evidence, the associated risk, the identification of individuals atrisk, the potential approach to reduce its impact and how should these athletes be informed.
Abstract: Exercise is, together with diet, a powerful health-promoting habit. However, an association of intense physical activity with the onset of atrial and ventricular arrhythmias, and sudden death has been described. Although initially questioned, the atrial pro-arrhythmic role of endurance physical activity is now well accepted in the scientific community. Atrial fibrillation is common among endurance athletes, being a source of morbidity in otherwise healthy young and middle-aged individuals. The mechanisms for its development are still poorly understood, but likely involve some components of the athlete's heart (e.g., bradycardia, atrial enlargement) and some clearly pathological factors (e.g., atrial fibrosis). Its management must be a careful balance between exercise moderation and cessation, as extremes in exercise practice have both been related to atrial fibrillation. In this article, we review the current knowledge on exercise-induced atrial fibrillation through different perspectives, each focusing on the epidemiological evidence, the associated risk, the identification of individuals at risk, the potential approach to reduce its impact and how should these athletes be informed.
7 citations
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TL;DR: It is shown that cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelial cells, suggesting an endothelial-mesenchymal transition (EndMT) similar to events that occur during formation of the atrioventricular cushion in the embryonic heart.
Abstract: Cardiac fibrosis, associated with a decreased extent of microvasculature and with disruption of normal myocardial structures, results from excessive deposition of extracellular matrix, which is mediated by the recruitment of fibroblasts. The source of these fibroblasts is unclear and specific anti-fibrotic therapies are not currently available. Here we show that cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelial cells, suggesting an endothelial-mesenchymal transition (EndMT) similar to events that occur during formation of the atrioventricular cushion in the embryonic heart. Transforming growth factor-β1 (TGF-β1) induced endothelial cells to undergo EndMT, whereas bone morphogenic protein 7 (BMP-7) preserved the endothelial phenotype. The systemic administration of recombinant human BMP-7 (rhBMP-7) significantly inhibited EndMT and the progression of cardiac fibrosis in mouse models of pressure overload and chronic allograft rejection. Our findings show that EndMT contributes to the progression of cardiac fibrosis and that rhBMP-7 can be used to inhibit EndMT and to intervene in the progression of chronic heart disease associated with fibrosis.
1,908 citations
TL;DR: Experimental CHF strongly promotes the induction of sustained AF by causing interstitial fibrosis that interferes with local conduction, with important potential implications for understanding, treating, and preventing AF related to CHF.
Abstract: Background—Studies of atrial fibrillation (AF) due to atrial tachycardia have provided insights into the remodeling mechanisms by which “AF begets AF” but have not elucidated the substrate that initially supports AF before remodeling occurs. We studied the effects of congestive heart failure (CHF), an entity strongly associated with clinical AF, on atrial electrophysiology in the dog and compared the results with those in dogs subjected to rapid atrial pacing (RAP; 400 bpm) with a controlled ventricular rate (AV block plus ventricular pacemaker at 80 bpm). Methods and Results—CHF induced by 5 weeks of rapid ventricular pacing (220 to 240 bpm) increased the duration of AF induced by burst pacing (from 8±4 seconds in control dogs to 535±82 seconds; P<0.01), similar to the effect of 1 week of RAP (713±300 seconds). In contrast to RAP, CHF did not alter atrial refractory period, refractoriness heterogeneity, or conduction velocity at a cycle length of 360 ms; however, CHF dogs had a substantial increase in th...
1,343 citations
TL;DR: Cultured fetal and adult human fibroblasts maintained key features of HOX gene expression patterns established during embryogenesis, suggesting that HOX genes may direct topographic differentiation and underlie the detailed positional memory in fibro Blasts.
Abstract: A fundamental feature of the architecture and functional design of vertebrate animals is a stroma, composed of extracellular matrix and mesenchymal cells, which provides a structural scaffold and conduit for blood and lymphatic vessels, nerves, and leukocytes. Reciprocal interactions between mesenchymal and epithelial cells are known to play a critical role in orchestrating the development and morphogenesis of tissues and organs, but the roles played by specific stromal cells in controlling the design and function of tissues remain poorly understood. The principal cells of stromal tissue are called fibroblasts, a catch-all designation that belies their diversity. We characterized genome-wide patterns of gene expression in cultured fetal and adult human fibroblasts derived from skin at different anatomical sites. Fibroblasts from each site displayed distinct and characteristic transcriptional patterns, suggesting that fibroblasts at different locations in the body should be considered distinct differentiated cell types. Notable groups of differentially expressed genes included some implicated in extracellular matrix synthesis, lipid metabolism, and cell signaling pathways that control proliferation, cell migration, and fate determination. Several genes implicated in genetic diseases were found to be expressed in fibroblasts in an anatomic pattern that paralleled the phenotypic defects. Finally, adult fibroblasts maintained key features of HOX gene expression patterns established during embryogenesis, suggesting that HOX genes may direct topographic differentiation and underlie the detailed positional memory in fibroblasts.
1,055 citations
TL;DR: The two PDGF null phenotypes reveal analogous morphogenetic functions for myofibroblast-type cells in lung and kidney organogenesis, and show that PDGF-B is required in the ontogeny of kidney mesangial cells.
854 citations
TL;DR: TGF-beta induces proliferation of connective tissue cells at low concentrations by stimulating autocrine PDGF-AA secretion, which at higher concentrations of TGF- beta, is decreased by down-regulation of PDGF receptor alpha subunits and perhaps by direct growth inhibition.
760 citations