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: This study focused on 55 genes from calcium signaling and 26 genes from extra cellular matrix ECM–receptor interaction that were found to be associated with the progression and recurrence of AF and identified central hub proteins according to random walk analysis derived scores representing interaction grade.
Abstract: Atrial fibrillation (AF) is a multifactorial disease with a strong genetic background. It is assumed that common and rare genetic variants contribute to the progression and recurrence of AF. The pathophysiological impact of those variants, especially when they are synonymous or non-coding, is often elusive and translation into functional experiments is difficult. In this study, we propose a method to go straight from genetic variants to defined gene targets. We focused on 55 genes from calcium signaling and 26 genes from extra cellular matrix ECM-receptor interaction that we found to be associated with the progression and recurrence of AF. These genes were mapped on protein-protein interaction data from three different databases. Based on the concept that central regulators are highly connected with their neighbors, we identified central hub proteins according to random walk analysis derived scores representing interaction grade. Our approach resulted in the identification of EGFR, RYR2, and PRKCA (calcium signaling) and FN1 and LAMA1 (ECM-receptor interaction) which represent promising targets for further functional characterization or pharmaceutical intervention.
14 citations
Cites background from "Differential Behaviors of Atrial Ve..."
...Laminin is involved in cardiac development and pathological remodeling (Schaper et al., 2002; Burstein et al., 2008)....
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...Laminin is a major component of ECM, especially the basement membrane, and was found to be expressed significantly higher in the left atrium compared to left ventricle (Burstein et al., 2008)....
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01 Jan 2015
TL;DR: This book will help to adapt the information that is gathered in order to translate it into treatments for fibrotic cardiac diseases and thus alter the course of their progression.
Abstract: Cardiac fibrosis is the pathological accumulation of cardiac extracellular matrix (ECM or matrix), which occurs in most types of heart disease Major recent advances in our understanding have allowed us to identify cardiac fibrosis as a primary disease independent of either cardiomyocyte injury or loss New developments within this field are burgeoning, including research that points to multiple sources for cardiac myofibroblasts participating in cardiovascular disease pathogenesis, the feasibility of bioengineered matrix tissues as well as the identification of novel targets to reduce the incidence and severity of cardiac fibrosis A summary of the state of knowledge of the regulation of the function of fibroblasts as well as a synopsis of the current state of investigation to address the biology of cardiovascular fibroblasts, valvular interstitial cells (VICs), and myofibroblasts is warranted This book will help to adapt the information that we have gathered in order to translate it into treatments for fibrotic cardiac diseases and thus alter the course of their progression
14 citations
TL;DR: The major findings of the existing computational studies investigating the implications of fibroblast-myocyte interactions in the normal and diseased heart are summarized and investigations into the potential role of voltage-dependent gap junctions in fibroblasts-myocytes interactions are presented.
Abstract: The adult heart is composed of a dense network of cardiomyocytes surrounded by nonmyocytes, the most abundant of which are cardiac fibroblasts. Several cardiac diseases, such as myocardial infarction or dilated cardiomyopathy, are associated with an increased density of fibroblasts, that is, fibrosis. Fibroblasts play a significant role in the development of electrical and mechanical dysfunction of the heart; however the underlying mechanisms are only partially understood. One widely studied mechanism suggests that fibroblasts produce excess extracellular matrix, resulting in collagenous septa. These collagenous septa slow propagation, cause zig-zag conduction paths, and decouple cardiomyocytes resulting in a substrate for arrhythmia. Another emerging mechanism suggests that fibroblasts promote arrhythmogenesis through direct electrical interactions with cardiomyocytes via gap junctions. Due to the challenges of investigating fibroblast-myocyte coupling in native cardiac tissue, computational modeling and in vitro experiments have facilitated the investigation into the mechanisms underlying fibroblast-mediated changes in cardiomyocyte action potential morphology, conduction velocity, spontaneous excitability, and vulnerability to reentry. In this paper, we summarize the major findings of the existing computational studies investigating the implications of fibroblast-myocyte interactions in the normal and diseased heart. We then present investigations from our group into the potential role of voltage-dependent gap junctions in fibroblast-myocyte interactions.
14 citations
TL;DR: A review of the evidence regarding direct effects of stretch on cardiac fibroblasts, specifically, the similarities and differences among studies in observed effects on cardiac-fibroblast function, the signaling-pathways implicated, and the factors that affect stretch-related phenotypes is presented in this paper.
Abstract: Atrial fibrillation (AF) is an important clinical problem. Chronic pressure/volume overload of the atria promotes AF, particularly via enhanced extracellular matrix (ECM) accumulation manifested as tissue fibrosis. Loading of cardiac cells causes cell-stretch that is generally considered to promote fibrosis by directly activating fibroblasts, the key cell-type responsible for ECM-production. The primary purpose of this article is to review the evidence regarding direct effects of stretch on cardiac fibroblasts, specifically: (i) the similarities and differences among studies in observed effects of stretch on cardiac-fibroblast function; (ii) the signaling-pathways implicated; and (iii) the factors that affect stretch-related phenotypes. Our review summarizes the most important findings and limitations in this area and gives an overview of clinical data and animal models related to cardiac stretch, with particular emphasis on the atria. We suggest that the evidence regarding direct fibroblast activation by stretch is weak and inconsistent, in part because of variability among studies in key experimental conditions that govern the results. Further work is needed to clarify whether, in fact, stretch induces direct activation of cardiac fibroblasts and if so, to elucidate the determining factors to ensure reproducible results. If mechanical load on fibroblasts proves not to be clearly profibrotic by direct actions, other mechanisms like paracrine influences, the effects of systemic mediators and/or the direct consequences of myocardial injury or death, might account for the link between cardiac stretch and fibrosis. Clarity in this area is needed to improve our understanding of AF pathophysiology and assist in therapeutic development.
13 citations
TL;DR: This review aims to summarize the methods used to assess left atrium structure and function, focusing on its role to identify subclinical and clinical cardiovascular disease and to provide additional prognostic information for stratifying high-risk subjects.
Abstract: Emerging evidence shows the clinical usefulness of left atrium analysis in different fields of cardiovascular medicine in terms of diagnosis, prognosis and as a potential target for medical treatment. Left atrium structural and functional remodeling has been shown to be a sensitive marker able to detect high-risk individuals in the general population and in subjects with known cardiovascular diseases such as atrial fibrillation, heart failure, ischemic heart disease and valvular heart disease. This review aims to summarize the methods used to assess left atrium structure and function, focusing on its role to identify subclinical and clinical cardiovascular disease and to provide additional prognostic information for stratifying high-risk subjects.
13 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