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: Investigation of the role of oxidative stress and related factors in tachycardia-induced atrial structural remodelling finds rapid activation in atrial myocytes promotes myofibril degradation through autocrine/paracrine TGF-β signalling and increased oxidative stress.
Abstract: Aims Atrial fibrillation (AF), a common tachyarrhythmia in clinical practice, is associated with increased oxidative stress. Structural remodeling in atrial myocytes, including myofibril degradation, is an important characteristic of AF. However, the mechanism underlying AF-induced cellular structural remodeling remains unclear. The aim of this study was to investigate the role of oxidative stress and related factors in tachycardia-induced atrial structural remodeling
Methods and results Cultured atrial-derived myocytes (HL-1 cell line) were subjected to electrical stimulation. Immunofluorescence and immunoblotting were used to evaluate oxidative stress, myofibril degradation, and transforming growth factor-β (TGF-β) expression. Tachypacing in HL-1 cells induced TGF-β expression, pronounced oxidative stress including up-regulation of NADPH oxidases (Nox2/4), and degradation of myofibril. Oxidative stress scavenger, NADPH oxidase inhibitors, and small-interfering RNAs for Nox2/4 blocked tachypacing-induced myofibril degradation, suggesting that Nox-derived oxidative stress may lead to tachycardia-induced myofibril degradation. Blockade of TGF-β signaling by neutralizing TGF-β antibodies attenuated myofibril loss in response to tachypacing, implicating autocrine and/or paracrine roles for TGF-β in such effects. Tachypacing also induced the activation of p-Smad3 (an effective mediator of TGF-β) and small-interfering RNAs for Nox2/4 attenuated its activation, supporting a crosstalk between both signaling pathways. Furthermore, TGF-β expression, oxidative stress, and myofibril loss were greater in the atria of patients with AF than those with sinus rhythm.
Conclusions Rapid activation in atrial myocytes promotes myofibril degradation through autocrine/paracrine TGF-β signaling and increased oxidative stress. These findings provide an important mechanistic insight into AF-related structural remodeling.
68 citations
TL;DR: Evaluating the potential role of CD44, a membrane receptor known to regulate fibrosis, and its related signaling in the pathogenesis of atrial fibrosis and AF found that blocking CD44-dependent signaling may be a feasible way for AF management.
Abstract: Atrial fibrillation (AF) is associated with atrial fibrosis. Inhibition of atrial fibrosis might be a plausible approach for AF prevention and therapy. This study is designed to evaluate the potential role of CD44, a membrane receptor known to regulate fibrosis, and its related signaling in the pathogenesis of atrial fibrosis and AF. Treatment of cultured rat atrial fibroblasts with transforming growth factor-β (TGF-β, a key mediator of atrial fibrosis) led to a higher expression of hyaluronan (HA), CD44, STAT3, and collagen (a principal marker of fibrosis) than that of ventricular fibroblasts. In vivo, TGF-β transgenic mice and AF patients exhibited a greater expression of HA, CD44, STAT3, and collagen in their atria than wild-type mice and sinus rhythm subjects, respectively. Treating TGF-β transgenic mice with an anti-CD44 blocking antibody resulted in a lower expression of STAT3 and collagen in their atria than those with control IgG antibody. Programmed stimulation triggered less AF episodes in TGF-β transgenic mice treated with anti-CD44 blocking antibody than in those with control IgG. Blocking CD44 signaling with anti-CD44 antibody and mutated CD44 plasmids attenuated TGF-β-induced STAT3 activation and collagen expression in cultured atrial fibroblasts. Deletion and mutational analysis of the collagen promoter along with chromatin immunoprecipitation demonstrated that STAT3 served as a vital transcription factor in collagen expression. TGF-β-mediated HA/CD44/STAT3 pathway plays a crucial role in the development of atrial fibrosis and AF. Blocking CD44-dependent signaling may be a feasible way for AF management.
68 citations
TL;DR: It is hoped that associated insight into myocyte-fibroblast coupling in the heart may lead to the discovery of novel therapeutic targets and the development of agents for improving outcomes of myocardial scarring and fibrosis.
68 citations
TL;DR: Genetically altered murine models of atrial fibrillation are reviewed to enable a better understanding of the mechanisms of AF and the assessment of novel therapeutic interventions.
Abstract: Understanding the mechanism of re-entrant arrhythmias in the past 30 years has allowed the development of almost curative therapies for many rhythm disturbances. The complex, polymorphic arrhythmias of atrial fibrillation and sudden death are, unfortunately, not yet well understood, and hence still in need of adequate therapy. Atrial fibrillation contributes markedly to morbidity and mortality in ageing Western populations. In the past decade, many genetically altered murine models have been described and characterised. Here, we review genetically altered murine models of atrial fibrillation; powerful tools that will enable a better understanding of the mechanisms of atrial fibrillation and the assessment of novel therapeutic interventions.
67 citations
Cites background from "Differential Behaviors of Atrial Ve..."
...The atria have been shown to be more susceptible to fibrotic remodeling (Burstein et al., 2008) and pacing of cultured atrial-derived myocytes was shown to increase expression of TGFβ1 (Yeh et al....
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TL;DR: The results show that functionally competent K+ channels are present in human atrial and ventricular TCs and their modulation may have significant implications in myocardial physiopathology.
Abstract: Telocytes (TCs) with exceptionally long cellular processes of telopodes have been described in human epicardium to act as structural supporting cells in the heart. We examined myocardial chamber-specific TCs identified in atrial and ventricular fibroblast culture using immunocytochemistry and studied their electrophysiological property by whole-cell patch clamp. Atrial and ventricular TCs with extended telopodes and alternating podoms and podomers that expressed CD34, c-Kit and PDGFR-β were identified. These cells expressed large conductance Ca2+-activated K+ current (BKCa) and inwardly rectifying K+ current (IKir), but not transient outward K+ current (Ito) and ATP-sensitive potassium current (KATP). The active channels were functionally competent with demonstrated modulatory response to H2S and transforming growth factor (TGF)-β1 whereby H2S significantly inhibited the stimulatory effect of TGF-β1 on current density of both BKCa and IKir. Furthermore, H2S attenuated TGF-β1-stimulated KCa1.1/Kv1.1 (encode BKCa) and Kir2.1 (encode IKir) expression in TCs. Our results show that functionally competent K+ channels are present in human atrial and ventricular TCs and their modulation may have significant implications in myocardial physiopathology.
61 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