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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Dissertation•
19 Nov 2018
TL;DR: The aim of the present study was to determine the link between atrial endothelial cells (AECs) senescence and the induction of pro-inflammatory, pro-adhesive, pro -fibrotic and pro-remodelling AECs patterns and also to evaluate the contribution of coagulation derived-factors such as thrombin.
Abstract: Many studies documented strong relationship between ageing and development of atrial fibrillation (AF). Moreover, it has been found that senescence and senescence-associated- secretory-phenotype play an important role in development of overall atrial inflammation which can ultimately ends up in atrial structural remodeling paving the way to AF perpetuation and maintenance. Moreover, it has been known for decades that AF has been associated with the activation of local and circulating coagulation factors. However, little is known about the impact of coagulation-derived factors, in particular thrombin, on the onset of AF. The aim of the present study was to determine the link between atrial endothelial cells (AECs) senescence and the induction of pro-inflammatory, pro-adhesive, pro-fibrotic and pro-remodelling AECs patterns and also to evaluate the contribution of coagulation derived-factors such as thrombin.
5 citations
Dissertation•
01 Jan 2015
TL;DR: Genetic variation in two chromosomal regions associated with AF influences local gene expression and Genetic Variation Associated With Low-Density Lipoprotein Cholesterol Levels Influences Zfhx3 Expression.
Abstract: P5841 ESC Congress 2014 (moderated poster) Martin RIR, Owens WA, Santibanez Koref M, Keavney BD. Heart. Genetic Risk Markers for Atrial Fibrillation Influence Allelic Expression of Nearby Candidate Genes. YIA4 Jun 2014;100 Suppl 3:A123-4. doi: 10.1136/heartjnl-2014-306118.227. British Cardiac Society 2014. (BAS/BSCR Young Investigator's Award runner up) Martin RIR, Glen E, Hall DH, Owens WA, Santibanez Koref M, Keavney BD. Genetic variation in two chromosomal regions associated with AF influences local gene expression. Europace. 2013: 15 suppl 2; ii119. doi:10.1093/europace/eut199 EHRA Europace 2013 (moderated poster) Martin RIR, Santibanez Koref M, Owens WA, Keavney BD. Genetic Variation Associated With Low-Density Lipoprotein Cholesterol Levels Influences Zfhx3 Expression. Heart. May 2013: 99 Suppl S2: A102-3. doi:10.1136/heartjnl-2013-304019.180 British Cardiac Society 2013 (moderated poster)
5 citations
TL;DR: A possible fibrosis-promoting role of BNP in the atrium is suggested, although the antifibrotic properties of B NP in the ventricle have been reported in previous studies, and the coordination between MMP-2 and SIRT1 in BNP-induced atrial myofibroblasts participates in atrial fibrosis.
5 citations
Dissertation•
17 Jun 2014
TL;DR: Dans un modele ovin de FA persistante, nous avons ainsi demontre that la frequence dominante (DF) de the FA augmentait progressivement pendant les premieres semaines de l’arythmie, alors que les episodes etaient paroxystiques, phenomene en rapport avec le raccourcissement de the duree du potentiel d’action secondaire au remodelage
Abstract: La fibrillation atriale (FA) est l’arythmie soutenue la plus frequente ; elle entraine une majoration significative de la morbidite et de la mortalite. Les mecanismes qui en sont responsables sont encore incompletement connus, et sa prise en charge n’est pas optimale. Afin de mieux comprendre la physiopathologie de la FA, nous avons mene differents travaux sur des coeurs de moutons isoles et perfuses par un systeme de Langendorff mais egalement en creant un modele chronique de FA persistante de longue duree. Dans un modele ovin de FA persistante, nous avons ainsi demontre que la frequence dominante (DF) de la FA augmentait progressivement pendant les premieres semaines de l’arythmie, alors que les episodes etaient paroxystiques, phenomene en rapport avec le raccourcissement de la duree du potentiel d’action secondaire au remodelage electrophysiologique. La DF se stabilisait des lors que la FA devenait persistante, une fois le remodelage electrophysiologique maximal. L’acceleration de la DF (dDF/dt) etait significativement correlee au temps necessaire a la transition vers la FA persistante. Le remodelage structurel n’apparaissait que secondairement, une fois l’arythmie devenue persistante. Sur le plan therapeutique, nous avons etudie les mecanismes anti-arythmiques de la chloroquine (bloqueur d’IK1) et de la ranolazine (bloqueur d’INa), molecules entrainant un ralentissement de la frequence de rotation des rotors, une diminution de la DF et un retour en rythme sinusal. Ces travaux nous ont permis de mieux apprehender le role des ces courants ioniques dans le maintien de la FA. Enfin, nous avons demontre l’efficacite de l’ablation de la FA en utilisant le cryoballon (CB) de deuxieme generation, efficacite grevee d’un taux de paresie du nerf phrenique eleve, dont nous avons pu predire la survenue a l’aide d’un predicteur simple, la distance entre le bord du CB et la catheter permettant de stimuler le nerf phrenique pendant l’application. Une meilleure comprehension des mecanismes a l’origine de l’initiation et du maintien de cette arythmie, ainsi qu’une meilleure prise en charge therapeutique permettraient d’ameliorer la qualite de vie des patients et d’en diminuer le taux de complications.
4 citations
TL;DR: This work introduces PlaqView 2.0 (www.plaqview.com), an open-source web portal for the exploration and analysis of published atherosclerosis single-cell datasets, which provides expanded features and functionalities as well as additional cardiovascular single- cell datasets.
Abstract: Single-cell RNA-seq (scRNA-seq) is a powerful genomics technology to interrogate the cellular composition and behaviors of complex systems. While the number of scRNA-seq datasets and available computational analysis tools have grown exponentially, there are limited systematic data sharing strategies to allow rapid exploration and re-analysis of single-cell datasets, particularly in the cardiovascular field. We previously introduced PlaqView, an open-source web portal for the exploration and analysis of published atherosclerosis single-cell datasets. Now, we introduce PlaqView 2.0 (www.plaqview.com), which provides expanded features and functionalities as well as additional cardiovascular single-cell datasets. We showcase improved PlaqView functionality, backend data processing, user-interface, and capacity. PlaqView brings new or improved tools to explore scRNA-seq data, including gene query, metadata browser, cell identity prediction, ad hoc RNA-trajectory analysis, and drug-gene interaction prediction. PlaqView serves as one of the largest central repositories for cardiovascular single-cell datasets, which now includes data from human aortic aneurysm, gene-specific mouse knockouts, and healthy references. PlaqView 2.0 brings advanced tools and high-performance computing directly to users without the need for any programming knowledge. Lastly, we outline steps to generalize and repurpose PlaqView's framework for single-cell datasets from other fields.
4 citations
References
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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