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Cardiac Fibroblasts (cardiac + fibroblast)
Kinds of Cardiac Fibroblasts Selected AbstractsIN VITRO INHIBITORY EFFECTS OF ATORVASTATIN ON CARDIAC FIBROBLASTS: IMPLICATIONS FOR VENTRICULAR REMODELLINGCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 9 2005Jennifer Martin SUMMARY 1.,Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) reduce mortality after myocardial infarction (MI). Although this may be predominantly due to their known anti-ischaemic actions, these drugs are known to have other beneficial effects. 2.,Because pathological deposition of extracellular matrix (ECM) material is a key component of remodelling after MI, we sought to determine whether atorvastatin could inhibit ECM production in vitro. 3.,The addition of atorvastatin to rat cardiac fibroblasts stimulated with either transforming growth factor (TGF)-,1 (TGF-,1) or angiotensin (Ang) II reduced collagen synthesis in a dose-dependent manner (3.7-fold reduction (95% confidence interval (CI) 1.8,15; P < 0.01) and 5.3-fold reduction (95% CI 1.8,7.7; P < 0.01), respectively, compared with stimulant alone). Similar observations were made in human cardiac fibroblast cell culture. Atorvastatin also dose-dependently reduced TGF-,1 and AngII-induced increases in ,(I)-procollagen mRNA (P < 0.01 for both), as well as gene expression of the profibrotic peptide connective tissue growth factor. 4.,Atorvastatin appears to directly inhibit collagen production by cardiac fibroblasts. This antifibrotic action may contribute to the antiremodelling effect of statins. [source] The origin of fibroblasts and mechanism of cardiac fibrosisJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2010Guido Krenning Fibroblasts are at the heart of cardiac function and are the principal determinants of cardiac fibrosis. Nevertheless, cardiac fibroblasts remain poorly characterized in molecular terms. Evidence is evolving that the cardiac fibroblast is a highly heterogenic cell population, and that such heterogeneity is caused by the distinct origins of fibroblasts in the heart. Cardiac fibroblasts can derive either from resident fibroblasts, from endothelial cells via an endothelial,mesenchynmal transition or from bone marrow-derived circulating progenitor cells, monocytes and fibrocytes. Here, we review the function and origin of fibroblasts in cardiac fibrosis.NB. The information given is correct. J. Cell. Physiol. 225: 631,637, 2010. © 2010 Wiley-Liss, Inc. [source] B-type natriuretic peptide and extracellular matrix protein interactions in human cardiac fibroblastsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2010Brenda K. Huntley Cardiac fibroblasts (CFs) regulate myocardial remodeling by proliferating, differentiating, and secreting extracellular matrix (ECM) proteins. B-type natriuretic peptide (BNP) is anti-fibrotic, inhibits collagen production, augments matrix metalloproteinases, and suppresses CF proliferation. Recently, we demonstrated that the ECM protein fibronectin (FN) augmented production of BNP's second messenger, 3,, 5, cyclic guanosine monophosphate (cGMP) in CFs, supporting crosstalk between FN, BNP, and its receptor, natriuretic peptide receptor A (NPR-A). Here, we address the specificity of FN to augment cGMP generation by investigating other matrix proteins, including collagen IV which contains RGD motifs and collagen I and poly- L -lysine, which have no RGD domain. Collagen IV showed increased cGMP generation to BNP similar to FN. Collagen I and poly- L -lysine had no effect. As FN also interacts with integrins, we then examined the effect of integrin receptor antibody blockade on BNP-mediated cGMP production. On FN plates, antibodies blocking RGD-binding domains of several integrin subtypes had little effect, while a non-RGD domain interfering integrin ,v,3 antibody augmented cGMP production. Further, on uncoated plates, integrin ,v,3 blockade continued to potentiate the BNP/cGMP response. These studies suggest that both RGD containing ECM proteins and integrins may interact with BNP/NPR-A to modulate cGMP generation. J. Cell. Physiol. 225: 251,255, 2010. © 2010 Wiley-Liss, Inc. [source] The origin of fibroblasts and mechanism of cardiac fibrosisJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2010Guido Krenning Fibroblasts are at the heart of cardiac function and are the principal determinants of cardiac fibrosis. Nevertheless, cardiac fibroblasts remain poorly characterized in molecular terms. Evidence is evolving that the cardiac fibroblast is a highly heterogenic cell population, and that such heterogeneity is caused by the distinct origins of fibroblasts in the heart. Cardiac fibroblasts can derive either from resident fibroblasts, from endothelial cells via an endothelial,mesenchynmal transition or from bone marrow-derived circulating progenitor cells, monocytes and fibrocytes. Here, we review the function and origin of fibroblasts in cardiac fibrosis.NB. The information given is correct. J. Cell. Physiol. 225: 631,637, 2010. © 2010 Wiley-Liss, Inc. [source] Role of hypoxia and cAMP in the transdifferentiation of human fetal cardiac fibroblasts: Implications for progression to scarring in autoimmune-associated congenital heart blockARTHRITIS & RHEUMATISM, Issue 12 2007Robert M. Clancy Objective Identification of isolated congenital heart block (CHB) predicts, with near certainty, the presence of maternal anti-SSA/Ro antibodies; however, the 2% incidence of CHB in first offspring of anti-SSA/Ro+ mothers, 20% recurrence in subsequent pregnancies, and discordance in identical twins suggest that an environmental factor amplifies the effect of the antibody. Accordingly, this study was carried out to explore the hypothesis that hypoxia potentiates a profibrosing phenotype of the fetal cardiac fibroblast. Methods Evidence of an effect of hypoxia was sought by immunohistologic evaluation of CHB-affected fetal heart tissue and by determination of erythropoietin levels in cord blood. The in vitro effect of hypoxia on gene expression and phenotype in fibroblasts derived from fetal hearts and lungs was investigated by Affymetrix arrays, quantitative polymerase chain reaction (PCR), immunofluorescence, and immunoblotting. Results In vivo hypoxic exposure was supported by the prominent intracellular fibroblast expression of hypoxia-inducible factor 1, in conduction tissue from 2 fetuses in whom CHB led to death. The possibility that hypoxia was sustained was suggested by significantly elevated erythropoietin levels in cord blood from CHB-affected, as compared with unaffected, anti-SSA/Ro,exposed neonates. In vitro exposure of cardiac fibroblasts to hypoxia resulted in transdifferentiation to myofibroblasts (a scarring phenotype), as demonstrated on immunoblots and immunofluorescence by increased expression of smooth muscle actin (SMA), an effect not seen in lung fibroblasts. Hypoxia-exposed cardiac fibroblasts expressed adrenomedullin at 4-fold increased levels, as determined by Affymetrix array, quantitative PCR, and immunofluorescence, thus focusing attention on cAMP as a modulator of fibrosis. MDL12,330A, an adenylate cyclase inhibitor that lowers the levels of cAMP, increased expression of fibrosis-related proteins (mammalian target of rapamycin, SMA, plasminogen activator inhibitor type 1, and type I collagen), while the cAMP activator forskolin attenuated transforming growth factor ,,elicited fibrosing end points in the cardiac fibroblasts. Conclusion These findings provide evidence that hypoxia may amplify the injurious effects of anti-SSA/Ro antibodies. Modulation of cAMP may be a key component in the scarring phenotype. Further assessment of the susceptibility of cardiac fibroblasts to cAMP modulation offers a new research direction in CHB. [source] Single mechano-gated channels activated by mechanical deformation of acutely isolated cardiac fibroblasts from ratsACTA PHYSIOLOGICA, Issue 3 2010A. Kamkin Abstract Aim:, Mechanosensitive conductances were reported in cardiac fibroblasts, but the properties of single channels mediating their mechanosensitivity remain uncharacterized. The aim of this work was to investigate single mechano-gated channels (MGCs) activated by mechanical deformations of cardiac fibroblasts. Methods:, Currents through single MGCs and mechanosensitive whole-cell currents were recorded from isolated rat atrial fibroblasts using the cell-attached and whole-cell patch-clamp configurations respectively. Defined mechanical stress was applied via the patch pipette used for the whole-cell recordings. Results:, Under resting conditions occasional short openings of two types of single MGCs with conductances of 43 and 87 pS were observed. Both types of channels displayed a linear current,voltage relationship with the reversal potential around 0 mV. Small (1 ,m) mechanical deformations affected neither single nor whole-cell mechano-gated currents. Cell compressions (2, 3 and 4 ,m) augmented the whole-cell currents and increased the frequency and duration of single channel openings. Cell stretches (2, 3 and 4 ,m) inactivated the whole-cell currents and abolished the activity of single MGCs. Gd3+ (8 ,m) blocked the whole-cell currents within 5 min. No single channel activity was observed in the cell-attached mode when Gd3+ was added to the intrapipette solution. Cytochalasin D and colchicine (100 ,m each) completely blocked both the whole-cell and single channel currents. Conclusions:, These findings show that rat atrial fibroblasts express two types of MGCs whose activity is governed by cell deformation. We conclude that fibroblasts can sense the direction of applied stress and contribute to mechano-electrical coupling in the heart. [source] Development of Live Cell Chips to Monitor Cell Differentiation ProcessesENGINEERING IN LIFE SCIENCES (ELECTRONIC), Issue 1 2008C. Maercker Abstract A big demand exists for high-throughput functional in vitro assays which can measure cellular phenotypes by molecular methods and therefore improve the resources of primary cells for cell therapy, tissue engineering and high-content screenings in drug development. This approach focuses on cellular adhesion which is an important differentiation process during homing of stem cells. Moreover, it is a promising method especially for adherent cells which are not accessible by classical cell sorting methods. The chip design includes a housing with electrodes to measure electric field densities and impedance, respectively. Moreover, specific coatings of the wells permit a perfect growth of the selected cell types. In parallel, protein biomarkers can be followed by light microscopy. So far, experiments have been started to discriminate between different cell densities and cell types. In addition, after stimulating human cardiac fibroblasts and human umbilical vein endothelial cells, concentrations of proteins involved in adhesion had been increased, and proteins were translocated within the cells. In ongoing experiments, different human cell lines and fibroblastoid mesenchymal stem cells isolated from fat tissue, umbilical cord, or bone marrow are tested in the chip. To optimize the adhesion conditions, the surfaces within the vials of the chip were specifically activated. Microscopy was adjusted to be able to measure cellular morphology in parallel. This concept allows to identify the behavior of mesenchymal stem cells, which cannot be described so far by standard biomarkers. In addition, simulation of the homing process of the cells within its stem cell niche in an in vitro assay is a promising setup for large-scale gain-of-function or loss-of-function screenings in functional genomics as well as for generating precursor cells relevant for the therapy of various diseases. [source] Fibrosis in heart disease: understanding the role of transforming growth factor-,1 in cardiomyopathy, valvular disease and arrhythmiaIMMUNOLOGY, Issue 1 2006Razi Khan Summary The importance of fibrosis in organ pathology and dysfunction appears to be increasingly relevant to a variety of distinct diseases. In particular, a number of different cardiac pathologies seem to be caused by a common fibrotic process. Within the heart, this fibrosis is thought to be partially mediated by transforming growth factor-,1 (TGF-,1), a potent stimulator of collagen-producing cardiac fibroblasts. Previously, TGF-,1 had been implicated solely as a modulator of the myocardial remodelling seen after infarction. However, recent studies indicate that dilated, ischaemic and hypertrophic cardiomyopathies are all associated with raised levels of TGF-,1. In fact, the pathogenic effects of TGF-,1 have now been suggested to play a major role in valvular disease and arrhythmia, particularly atrial fibrillation. Thus far, medical therapy targeting TGF-,1 has shown promise in a multitude of heart diseases. These therapies provide great hope, not only for treatment of symptoms but also for prevention of cardiac pathology as well. As is stated in the introduction, most reviews have focused on the effects of cytokines in remodelling after myocardial infarction. This article attempts to underline the significance of TGF-,1 not only in the post-ischaemic setting, but also in dilated and hypertrophic cardiomyopathies, valvular diseases and arrhythmias (focusing on atrial fibrillation). It also aims to show that TGF-,1 is an appropriate target for therapy in a variety of cardiovascular diseases. [source] The origin of fibroblasts and mechanism of cardiac fibrosisJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2010Guido Krenning Fibroblasts are at the heart of cardiac function and are the principal determinants of cardiac fibrosis. Nevertheless, cardiac fibroblasts remain poorly characterized in molecular terms. Evidence is evolving that the cardiac fibroblast is a highly heterogenic cell population, and that such heterogeneity is caused by the distinct origins of fibroblasts in the heart. Cardiac fibroblasts can derive either from resident fibroblasts, from endothelial cells via an endothelial,mesenchynmal transition or from bone marrow-derived circulating progenitor cells, monocytes and fibrocytes. Here, we review the function and origin of fibroblasts in cardiac fibrosis.NB. The information given is correct. J. Cell. Physiol. 225: 631,637, 2010. © 2010 Wiley-Liss, Inc. [source] B-type natriuretic peptide and extracellular matrix protein interactions in human cardiac fibroblastsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2010Brenda K. Huntley Cardiac fibroblasts (CFs) regulate myocardial remodeling by proliferating, differentiating, and secreting extracellular matrix (ECM) proteins. B-type natriuretic peptide (BNP) is anti-fibrotic, inhibits collagen production, augments matrix metalloproteinases, and suppresses CF proliferation. Recently, we demonstrated that the ECM protein fibronectin (FN) augmented production of BNP's second messenger, 3,, 5, cyclic guanosine monophosphate (cGMP) in CFs, supporting crosstalk between FN, BNP, and its receptor, natriuretic peptide receptor A (NPR-A). Here, we address the specificity of FN to augment cGMP generation by investigating other matrix proteins, including collagen IV which contains RGD motifs and collagen I and poly- L -lysine, which have no RGD domain. Collagen IV showed increased cGMP generation to BNP similar to FN. Collagen I and poly- L -lysine had no effect. As FN also interacts with integrins, we then examined the effect of integrin receptor antibody blockade on BNP-mediated cGMP production. On FN plates, antibodies blocking RGD-binding domains of several integrin subtypes had little effect, while a non-RGD domain interfering integrin ,v,3 antibody augmented cGMP production. Further, on uncoated plates, integrin ,v,3 blockade continued to potentiate the BNP/cGMP response. These studies suggest that both RGD containing ECM proteins and integrins may interact with BNP/NPR-A to modulate cGMP generation. J. Cell. Physiol. 225: 251,255, 2010. © 2010 Wiley-Liss, Inc. [source] BNP-induced activation of cGMP in human cardiac fibroblasts: Interactions with fibronectin and natriuretic peptide receptorsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2006Brenda K. Huntley Cardiac remodeling involves the accumulation of extracellular matrix (ECM) proteins including fibronectin (FN). FN contains RGD motifs that bind integrins at DDX sequences allowing signaling from the ECM to the nucleus. We noted that the natriuretic peptide receptor A (NPR-A) sequence contains both RGD and DDX sequences. The goal of the current investigation was to determine potential interactions between FN and NPR-A on BNP induction of cGMP in cultured human cardiac fibroblasts (CFs). Further, we sought to determine whether a Mayo designed NPR-A specific RGD peptide could modify this interaction. Here we reconfirm the presence of all three natriuretic peptide receptors (NPR) in CFs. CFs plated on FN demonstrated a pronounced increase in cGMP production to BNP compared to non-coated plates. This production was also enhanced by the NPR-A specific RGD peptide, which further augmented FN associated cGMP production. Addition of HS-142-1, a NPR-A/B antagonist, abrogated the responses of BNP to both FN and the NPR-A specific RGD peptide. Finally, we defined a possible role for the NPR-C through non-cGMP mechanisms in mediating the anti-proliferative actions of BNP in CFs where the NPR-C antagonist cANF 4-28 but not HS-142-1 blocked BNP-mediated inhibition of proliferation of CFs. We conclude that NPR-A interacts with components of the ECM such as FN to enhance BNP activation of cGMP and that a small NPR-A specific RGD peptide augments this action of BNP with possible therapeutic implications. Lastly, the NPR-C may also have a role in mediating anti-proliferative actions of BNP in CFs. J. Cell. Physiol. 209: 943,949, 2006. © 2006 Wiley-Liss, Inc. [source] TNF Receptors Differentially Signal and Are Differentially Expressed and Regulated in the Human HeartAMERICAN JOURNAL OF TRANSPLANTATION, Issue 12 2009R. S. Al-Lamki Tumor necrosis factor (TNF) utilizes two receptors, TNFR1 and 2, to initiate target cell responses. We assessed expression of TNF, TNFRs and downstream kinases in cardiac allografts, and compared TNF responses in heart organ cultures from wild-type (WTC57BL/6), TNFR1-knockout (KO), TNFR2KO, TNFR1/2KO mice. In nonrejecting human heart TNFR1 was strongly expressed coincidentally with inactive apoptosis signal-regulating kinase-1 (ASK1) in cardiomyocytes (CM) and vascular endothelial cells (VEC). TNFR2 was expressed only in VEC. Low levels of TNF localized to microvessels. Rejecting cardiac allografts showed increased TNF in microvessels, diminished TNFR1, activation of ASK1, upregulated TNFR2 co-expressed with activated endothelial/epithelial tyrosine kinase (Etk), increased apoptosis and cell cycle entry in CM. Neither TNFR was expressed significantly by cardiac fibroblasts. In WTC57BL/6 myocardium, TNF activated both ASK1 and Etk, and increased both apoptosis and cell cycle entry. TNF-treated TNFR1KO myocardium showed little ASK1 activation and apoptosis but increased Etk activation and cell cycle entry, while TNFR2KO myocardium showed little Etk activation and cell cycle entry but increased ASK1 activation and apoptosis. These observations demonstrate independent regulation and differential functions of TNFRs in myocardium, consistent with TNFR1-mediated cell death and TNFR2-mediated repair. [source] Role of hypoxia and cAMP in the transdifferentiation of human fetal cardiac fibroblasts: Implications for progression to scarring in autoimmune-associated congenital heart blockARTHRITIS & RHEUMATISM, Issue 12 2007Robert M. Clancy Objective Identification of isolated congenital heart block (CHB) predicts, with near certainty, the presence of maternal anti-SSA/Ro antibodies; however, the 2% incidence of CHB in first offspring of anti-SSA/Ro+ mothers, 20% recurrence in subsequent pregnancies, and discordance in identical twins suggest that an environmental factor amplifies the effect of the antibody. Accordingly, this study was carried out to explore the hypothesis that hypoxia potentiates a profibrosing phenotype of the fetal cardiac fibroblast. Methods Evidence of an effect of hypoxia was sought by immunohistologic evaluation of CHB-affected fetal heart tissue and by determination of erythropoietin levels in cord blood. The in vitro effect of hypoxia on gene expression and phenotype in fibroblasts derived from fetal hearts and lungs was investigated by Affymetrix arrays, quantitative polymerase chain reaction (PCR), immunofluorescence, and immunoblotting. Results In vivo hypoxic exposure was supported by the prominent intracellular fibroblast expression of hypoxia-inducible factor 1, in conduction tissue from 2 fetuses in whom CHB led to death. The possibility that hypoxia was sustained was suggested by significantly elevated erythropoietin levels in cord blood from CHB-affected, as compared with unaffected, anti-SSA/Ro,exposed neonates. In vitro exposure of cardiac fibroblasts to hypoxia resulted in transdifferentiation to myofibroblasts (a scarring phenotype), as demonstrated on immunoblots and immunofluorescence by increased expression of smooth muscle actin (SMA), an effect not seen in lung fibroblasts. Hypoxia-exposed cardiac fibroblasts expressed adrenomedullin at 4-fold increased levels, as determined by Affymetrix array, quantitative PCR, and immunofluorescence, thus focusing attention on cAMP as a modulator of fibrosis. MDL12,330A, an adenylate cyclase inhibitor that lowers the levels of cAMP, increased expression of fibrosis-related proteins (mammalian target of rapamycin, SMA, plasminogen activator inhibitor type 1, and type I collagen), while the cAMP activator forskolin attenuated transforming growth factor ,,elicited fibrosing end points in the cardiac fibroblasts. Conclusion These findings provide evidence that hypoxia may amplify the injurious effects of anti-SSA/Ro antibodies. Modulation of cAMP may be a key component in the scarring phenotype. Further assessment of the susceptibility of cardiac fibroblasts to cAMP modulation offers a new research direction in CHB. [source] IN VITRO INHIBITORY EFFECTS OF ATORVASTATIN ON CARDIAC FIBROBLASTS: IMPLICATIONS FOR VENTRICULAR REMODELLINGCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 9 2005Jennifer Martin SUMMARY 1.,Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) reduce mortality after myocardial infarction (MI). Although this may be predominantly due to their known anti-ischaemic actions, these drugs are known to have other beneficial effects. 2.,Because pathological deposition of extracellular matrix (ECM) material is a key component of remodelling after MI, we sought to determine whether atorvastatin could inhibit ECM production in vitro. 3.,The addition of atorvastatin to rat cardiac fibroblasts stimulated with either transforming growth factor (TGF)-,1 (TGF-,1) or angiotensin (Ang) II reduced collagen synthesis in a dose-dependent manner (3.7-fold reduction (95% confidence interval (CI) 1.8,15; P < 0.01) and 5.3-fold reduction (95% CI 1.8,7.7; P < 0.01), respectively, compared with stimulant alone). Similar observations were made in human cardiac fibroblast cell culture. Atorvastatin also dose-dependently reduced TGF-,1 and AngII-induced increases in ,(I)-procollagen mRNA (P < 0.01 for both), as well as gene expression of the profibrotic peptide connective tissue growth factor. 4.,Atorvastatin appears to directly inhibit collagen production by cardiac fibroblasts. This antifibrotic action may contribute to the antiremodelling effect of statins. [source] | |||||||||||||