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: In this article, an asymptotic theory of propagation and block of electrical excitation in a model of atrial tissue with myocyte-fibroblast coupling is presented.
Abstract: The electrical coupling between myocytes and fibroblasts and the spacial distribution of fibroblasts within myocardial tissues are significant factors in triggering and sustaining cardiac arrhythmias, but their roles are poorly understood. This article describes both direct numerical simulations and an asymptotic theory of propagation and block of electrical excitation in a model of atrial tissue with myocyte-fibroblast coupling. In particular, three idealized fibroblast distributions are introduced: uniform distribution, fibroblast barrier and myocyte strait-all believed to be constituent blocks of realistic fibroblast distributions. Primary action potential biomarkers including conduction velocity, peak potential and triangulation index are estimated from direct simulations in all cases. Propagation block is found to occur at certain critical values of the parameters defining each idealized fibroblast distribution, and these critical values are accurately determined. An asymptotic theory proposed earlier is extended and applied to the case of a uniform fibroblast distribution. Biomarker values are obtained from hybrid analytical-numerical solutions of coupled fast-time and slow-time periodic boundary value problems and compare well to direct numerical simulations. The boundary of absolute refractoriness is determined solely by the fast-time problem and is found to depend on the values of the myocyte potential and on the slow inactivation variable of the sodium current ahead of the propagating pulse. In turn, these quantities are estimated from the slow-time problem using a regular perturbation expansion to find the steady state of the coupled myocyte-fibroblast kinetics. The asymptotic theory gives a simple analytical expression that captures with remarkable accuracy the block of propagation in the presence of fibroblasts.
4 citations
Dissertation•
01 Jan 2013
4 citations
Dissertation•
01 Jan 2009
TL;DR: In this article, annees, des etudes ont revele un role important of ces cellules dans le fonctionnement normal et pathologique du coeur.
Abstract: Dans le coeur, les fibroblastes representent la population cellulaire majoritaire en nombre. Ces dernieres annees, des etudes ont revele un role important de ces cellules dans le fonctionnement normal et pathologique du coeur. Les fibroblastes sont physiologiquement la source de nombreux facteurs autocrines et paracrines. Ils sont egalement a la base du renouvellement de la matrice extra-cellulaire (MEC). En reponse a un stress pathologique, ils peuvent subir un processus de differenciation en myofibroblastes et une alteration de leurs proprietes et de leur fonction a l'origine d'un dysfonctionnement cardiaque. Bien que les fibroblastes soient consideres comme des cellules non excitables, des etudes ont revele ces dernieres annees l'expression fonctionnelle de differents canaux ioniques sur leur membrane. L'objectif de ma these a ete d'une part de caracteriser au niveau moleculaire et fonctionnel de nouvelles conductances dans les fibroblastes cardiaques et d'autre part d'evaluer leur impact sur les proprietes fonctionnelles de ces cellules. Un criblage par PCR a haut rendement a permis de reveler l'expression d'un ensemble de genes codant des sous-unites canalaires dans les fibroblastes cardiaques. Parmi ces genes, ceux codant les sous-unites SUR2 et Kir6. 1 ont le niveau d'expression le plus eleve. L'association des unites SUR2 et Kir6. 1 etant connue pour former un canal potassique, nous avons focalise notre interet sur ces deux sous-unites. Des analyses par western-blot ont montre une augmentation progressive de l'expression des unites SUR2 et Kir6. 1 au cours de la differenciation des fibroblastes en myofibroblastes. Des enregistrements en patch-clamp en configuration « inside-out » ont revele l'activite d'un canal potassique, insensible a l’ATP mais inhibe par le glibenclamide et active par l'UDP et le pinacidil. Ce canal possede des caracteristiques similaires au canal de type SUR2/Kir6. 1 decrit pour la premiere fois par Yamada et collaborateurs en 1997. Au niveau macroscopique des enregistrements en patchclamp en cellule entiere ont permis de mettre en evidence la fonctionnalite d'un courant potassique active par le pinacidil et sensible au glibenclamide. De plus l'expression fonctionnelle de ce courant est concomitante avec l'expression proteique des sous-unites SUR2 et Kir6. 1. La sphingosine-1-phosphate (S1P), un sphingolipide fortement secrete en condition pathologique est egalement capable d'activer cette conductance par l'intermediaire du recepteur de type 3 a la S1P (S1P3) et ce a des concentrations de l'ordre du nM. L'activation du canal SUR2/Kir6. 1 par le pinacidil ou par la S1P est capable de stimuler la proliferation et de diminuer la secretion d’IL-6 et de collagene. En revanche la S1P est egalement capable de stimuler la migration par l'intermediaire du S1P3 mais independemment du canal SUR2/Kir6. 1. Parallelement a ces resultats obtenus sur la souris, des experiences preliminaires suggerent la presence de cette conductance dans des fibroblastes auriculaires humains. En conclusion, ce travail a permis de mettre en evidence pour la premiere fois dans les fibroblastes cardiaques une conductance potassique sensible au glibenclamide lors de la differenciation des fibroblastes en myofibroblastes et dont la modulation pourrait influer sur la physiopathologie cardiaque.
4 citations
Cites background from "Differential Behaviors of Atrial Ve..."
...En effet il a été montré des différences morphologiques et fonctionnelles entre les fibroblastes auriculaires et ventriculaires (Burstein et al., 2008)....
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...Figure I-14 : Mécanismes de régulation moléculaire autocrines et paracrines à l’origine de la fibrose Modifié d’après Burstein et al, 2008 Cardiomyocyte AT-R TGFβ-R Fibroblaste Connexine FIBROSE Synthèse collagène et protéines de la MEC c Conséquences fonctionnelles La fibrose ventriculaire altère…...
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...Ils sont fusiformes et étalés et on observe des prolongements cytoplasmiques typiques (Burstein et al., 2008)....
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01 Jan 2014
4 citations
TL;DR: The findings provide a novel understanding of the molecular differences between human atrial and ventricular myocardium and may establish a framework for an anatomically detailed evaluation of cardiac function regulation.
Abstract: Human atrial and ventricular myocardium has distinct structure and physiology. MicroRNAs (miRNAs) are the central players in the regulation of gene expression, participating in many physiological processes. A comprehensive knowledge of miRNA expression in the human heart is essential for the understanding of myocardial function. The aim of this study was to compare the miRNA signature in human right atrial and ventricular myocardium. Agilent human miRNA arrays were used to indicate the miRNA expression signatures of the right atrial (n = 8) and ventricular (n = 9) myocardium of healthy individuals. Quantitative reverse transcription-polymerase chain reactions (qRT-PCRs) were used to validate the array results. DIANA-mirPath was used to incorporate the miRNAs into pathways. MiRNA arrays showed that 169 miRNAs were expressed at different levels in human right atrial and ventricular myocardium. The unsupervised hierarchical clustering analysis based on the 169 dysregulated miRNAs showed that miRNA expression categorized two well-defined clusters that corresponded to human right atrial and ventricular myocardium. The qRT-PCR results correlated well with the microarray data. Bioinformatic analysis indicated the potential miRNA targets and molecular pathways. This study indicates that distinct miRNA expression signatures in human right atrial and ventricular myocardium. The findings provide a novel understanding of the molecular differences between human atrial and ventricular myocardium and may establish a framework for an anatomically detailed evaluation of cardiac function regulation.
4 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