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Journal ArticleDOI

Differential Behaviors of Atrial Versus Ventricular Fibroblasts A Potential Role for Platelet-Derived Growth Factor in Atrial-Ventricular Remodeling Differences

01 Apr 2008-Circulation (Lippincott Williams & Wilkins)-Vol. 117, Iss: 13, pp 1630-1641
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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Citations
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Journal ArticleDOI
TL;DR: Reduced MK5 expression alters fibroblast function and scar morphology but not mortality post-MI, and reduces infarct size, scar area, and scar collagen content post-myocardial infarction.
Abstract: MK5/PRAK is a protein serine/threonine kinase activated by p38 MAPK and/or atypical MAPKs ERK3/4. MK5 haplodeficiency reduced infarct size, scar area, and scar collagen content post-myocardial infa...

10 citations

Journal ArticleDOI
TL;DR: P preferential fibrosis might play an important role in the arrhythmogenic substrate of AF in HT rat hearts and its effect on promoting AF in hypertensive (HT) rat hearts was determined.

9 citations

Journal ArticleDOI
TL;DR: An elevated preoperative plasma ET-1 level can be used as a predictor of postoperative atrial fibrillation (POAF) after mitral valve surgery.
Abstract: OBJECTIVES This study analysed the association between endothelin-1 (ET-1) and left atrial dimension (LAD) and evaluated whether ET-1 can be a predictor of postoperative atrial fibrillation (POAF) after mitral valve surgery. METHODS This is a prospective study that enrolled 80 patients who underwent isolated mitral valve surgery. Plasma concentrations of ET-1 from peripheral venous blood were tested. POAF was detected using a telemetry strip or 12-lead electrocardiogram until the time of discharge. RESULTS Patients undergoing mitral valve surgery with preoperative sinus rhythm (n = 80; average age 63.9 ± 7.9 years) were recruited to this study. POAF was documented in 31 (38.8%) patients. Preoperative plasma ET-1 levels were higher in patients with POAF compared to those without POAF (2.23 ± 0.67 vs 1.68 ± 0.59 pg/ml; P < 0.001). The plasma concentrations of ET-1 were positively correlated with LAD (Pearson's r = 0.421; P < 0.001). Multivariate logistic regression analysis revealed that LAD (odds ratio 1.170, 95% confidence interval 1.039-1.317; P = 0.009) and preoperative plasma ET-1 levels (upper versus lower 50th percentile: odds ratio 3.713, 95% confidence interval 1.085-12.701; P = 0.037) were predictors of POAF after mitral valve surgery. CONCLUSIONS Plasma levels of ET-1 were positively correlated with LAD in patients with mitral valve disease. An elevated preoperative plasma ET-1 level can be used as a predictor of POAF after mitral valve surgery.

9 citations

Journal ArticleDOI
TL;DR: It is concluded that TRPM4 participates in fibroblast growth and could thus be involved in cardiac fibrosis.
Abstract: Cardiac fibroblasts play an important role in cardiac matrix turnover and are involved in cardiac fibrosis development. Ca2+ is a driving belt in this phenomenon. This study evaluates the functional expression and contribution of the Ca2+-activated channel TRPM4 in atrial fibroblast phenotype. Molecular and electrophysiological investigations were conducted in human atrial fibroblasts in primary culture and in atrial fibroblasts obtained from wild-type and transgenic mice with disrupted Trpm4 gene (Trpm4−/−). A typical TRPM4 current was recorded on human cells (equal selectivity for Na+ and K+, activation by internal Ca2+, voltage sensitivity, conductance of 23.2 pS, inhibition by 9-phenanthrol (IC50 = 6.1 × 10−6 mol L−1)). Its detection rate was 13% on patches at days 2–4 in culture but raised to 100% on patches at day 28. By the same time, a cell growth was observed. This growth was smaller when cells were maintained in the presence of 9-phenanthrol. Similar cell growth was measured on wild-type mice atrial fibroblasts during culture. However, this growth was minimized on Trpm4−/− mice fibroblasts compared to control animals. In addition, the expression of alpha smooth muscle actin increased during culture of atrial fibroblasts from wild-type mice. This was not observed in Trpm4−/− mice fibroblasts. It is concluded that TRPM4 participates in fibroblast growth and could thus be involved in cardiac fibrosis.

9 citations

Book ChapterDOI
TL;DR: This review highlights the significance of telocytes in such connectivity and conductivity within the interstitial bioelectric network in tissue homeostasis.
Abstract: The heart is an electrically conducting organ with networked bioelectric currents that transverse a large segment of interstitial space interspersed with the muscular parenchyma. Non-excitable connective cells in the interstitial space contributed importantly to many structural, biochemical, and physiological activities of cardiac homeostasis. However, contribution of interstitial cells in the cardiac niche has long been neglected. Telocyte is recently recognized as a distinct class of interstitial cell that resides in a wide array of tissues including in the epicardium, myocardium, and endocardium of the heart. They are increasingly described to conduct ionic currents that may have significant implications in bioelectric signaling. In this review, we highlight the significance of telocytes in such connectivity and conductivity within the interstitial bioelectric network in tissue homeostasis.

9 citations

References
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Journal ArticleDOI
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

Journal ArticleDOI
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

Journal ArticleDOI
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

Journal ArticleDOI
14 Jun 1996-Cell
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

Journal ArticleDOI
02 Nov 1990-Cell
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