CTGF Expression is Induced by TGF- β in Cardiac Fibroblasts and Cardiac Myocytes: a Potential Role in Heart Fibrosis

Chen, Michelle; Lam, Andrew; Abraham, Judith A.; Schreiner, George F.; Joly, Alison

doi:10.1006/jmcc.2000.1215

Cited by 408 publications

(367 citation statements)

References 30 publications

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“…Interestingly, Ang II alone, even at micromolar concentrations, has little if any effect on CTGF mRNA level in cardiac fibroblasts. 49 Previously we have shown that in dTGR, Ang II-mediated leukocyte infiltration and adhesion molecule overexpression are due to Ang II-induced ROS formation and activation of the redox-sensitive transcription factors NF-B and AP-1. 50 Very recently, we showed that Ang II controls the migration of mature dendritic MHC II-positive cells whose maturation process seemed to be controlled by TNF␣.…”

Section: Discussionmentioning

confidence: 95%

Angiotensin II Induces Connective Tissue Growth Factor Gene Expression via Calcineurin-Dependent Pathways

Finckenberg

Inkinen

Ahonen

et al. 2003

The American Journal of Pathology

102

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Connective tissue growth factor (CTGF) is a polypeptide implicated in the extracellular matrix synthesis.Previous studies have provided evidence that angiotensin II (Ang II) promotes collagen synthesis and regulates collagen degradation. We investigated whether or not CTGF mediates the profibrotic effects of Ang II in the heart and kidneys and the role of calcineurin-dependent pathways in CTGF gene regulation. In transgenic rats harboring human renin and angiotensinogen genes, Ang II induced an age-dependent increase in myocardial CTGF expression, which was 3.5-fold greater compared to normotensive Sprague Dawley (SD) rats. CTGF overexpression correlated closely with the Ang II-induced rise in blood pressure. CTGF mRNA and protein were located predominantly in areas with leukocyte infiltration, myocardial, and vascular lesions and co-localized with TGF␤ 1 , collagen I, and collagen III mRNA expressions. Ang II induced CTGF mRNA and protein to a lesser extent in the kidneys, predominantly in glomeruli, arterioles, and in the interstitium with ample inflammation. However, no expression was found in the right ventricle or pulmonary arteries. Blockade of calcineurin activity by cyclosporine A completely normalized Ang II-induced CTGF overexpression in heart and kidney, suppressed the inflammatory response, and mitigated Ang II-induced cell proliferation and apoptosis. In contrast, blockade of mTOR (target of rapamycin) pathway by everolimus, further increased the expression of CTGF even though everolimus ameliorated cell proliferation and T-cellmediated inflammation. Our findings provide evidence that CTGF mediates Ang II-induced fibrosis in the heart and kidneys via blood pressure and cal-

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Section: Discussionmentioning

confidence: 95%

Angiotensin II Induces Connective Tissue Growth Factor Gene Expression via Calcineurin-Dependent Pathways

Finckenberg

Inkinen

Ahonen

et al. 2003

The American Journal of Pathology

102

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“…32,34,35,42,63 There seems to be signal redundancy, in which both Smad-dependent and Smad-independent pathways are involved in TGF-␤1-mediated responses in cardiac fibroblasts; however, the key signal transducers are T␤Rs. As shown in Figure 2E, when compared with fibroblasts isolated from young mice, the fibroblasts generated from aged cardiac MSCs exhibit reduced T␤RI and T␤RII expression and, therefore, demonstrate reduced responsiveness to TGF-␤1, which translates into decreased phosphorylation of 30 minutes of activation with 10 ng/mL TGF-␤1 in cardiac fibroblasts isolated from young (4 months old) and aged (30 months old) mice. B: p38MAPK activation depends on synergistic action of TGF-␤1 and AICAR.…”

Section: Discussionmentioning

confidence: 98%

“…Quiescent cultured cardiac fibroblasts derived from young animals when treated with TGF-␤1 for 24 hours demonstrated increased expression of connective tissue growth factor and collagen type 1 by twofold to threefold, in agreement with the findings of others. 29,30 In contrast, fibroblasts derived from 30-month-old mice cultured under the same conditions as the young fibroblasts demonstrated no substantial increase in connective tissue growth factor and collagen type 1 mRNA expression in response to TGF-␤1 ( Figure 2A). It has been previously demonstrated that 24-monthold mice exhibit reduced collagen deposition after MI.…”

Section: Progenitor Cells Isolated From Aged Animals Differentiate Inmentioning

confidence: 97%

Defective Myofibroblast Formation from Mesenchymal Stem Cells in the Aging Murine Heart

Cieslik

Trial

Entman

2011

The American Journal of Pathology

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Cardiac fibroblasts are the most prevalent cell type in the heart. These cells exert a critical role in regulating normal myocardial function and in the adverse myocardial remodeling that occurs after myocardial infarction (MI). 1 Irreversible cardiomyocyte damage owing to cessation of oxygen supply during MI leads to necrosis, which stimulates inflammatory reactions that trigger reparative pathways and activate cells to form a scar. Cytokines released by inflammatory infiltrating leukocytes promote endogenous mesenchymal stem cell (MSC) proliferation and migration toward the infarct site, followed by differentiation into fibroblasts that deposit scar-forming collagen. The fibroblasts mature into myofibroblasts, expressing scar-contracting ␣-smooth muscle actin (␣-SMA). 2 Resident fibroblasts also become activated and participate in this process. After several weeks, a mature scar is formed, and most of the myofibroblasts undergo apoptosis. [3][4][5] We have previously established in a model of mouse MI that, compared with young animals, aged mice demonstrate greater infarct expansion and less effective myocardial repair. 6 Defective scar formation arises from a decreased number of myofibroblasts and diminished collagen deposition in the infarct, which results in a structurally unstable scar formed by loose connective tissue. 7 Evidence indicates that multipotent cells can be generated in vitro from several adult organs including the heart. 8 Tissue-resident progenitor cells of mesenchymal origin can differentiate into myogenic, adipocytic, chondrocytic, osteoblastic, and fibroblastic lineages. 9 -11 The potential of those stem cells to differentiate decreases

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“…This statement notwithstanding, we cannot exclude a potential contributory role for Smad independent pro-fibrotic mechanisms, including activation of extracellular signal-regulated kinase, 30 the Rho/Rho-kinase signaling pathway, 31 and connective tissue growth factor. 32,33 Although TGF-β mediated signaling has been shown to be important in myocardial fibrosis, it is worth noting a recent study in transgenic mice with cardiac restricted overexpression of a constitutively active TGF-β 1 mutant, which showed that the expression of this constitutively active mutant did lead to the development of ventricular fibrosis. 34 Moreover, fibrosis was not observed in hearts engrafted with skeletal myoblasts expressing high levels of TGF-β 1 .…”

Section: Tgf-β Signaling and Myocardial Fibrosismentioning

confidence: 99%

Transforming growth factor-β receptor antagonism attenuates myocardial fibrosis in mice with cardiac-restricted overexpression of tumor necrosis factor

Sakata¹,

Chancey²,

Divakaran³

et al. 2007

Basic Res Cardiol

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The mechanisms that are responsible for the development of myocardial fibrosis in the inflammatory cardiomyopathy are unknown. Previously we have generated lines of transgenic mice with cardiac restricted overexpression of tumor necrosis factor (MHCsTNF mice), a proinflammatory cytokine. The MHCsTNF mice develop a heart failure phenotype that is characterized by progressive myocardial fibrosis, as well as increase levels transforming growth factor-β (TGF-β) mRNA and protein. In order to determine whether TGF-β mediated signaling was responsible for the myocardial fibrosis observed in the MHCsTNF mice, we treated MHCsTNF and littermate control mice from 4 to 12 weeks of age with a novel orally available TGF-β receptor antagonist (NP-40208). At the time of terminal study myocardial collagen content was determined using the picrosirius red technique, and LV systolic and diastolic function were determined using the Langendorff method. Treatment with NP-40208 resulted in a significant decrease in the nuclear translocation of Smad 2/3, a decrease in heart-weight to body-weight ratio, decreased fibrillar collagen content and decreased LV chamber stiffness in the MHCsTNF mice when compared to diluent treated controls. Treatment with NP-40208 had no discernable effect on LV systolic function, nor any effect on fetal gene expression in the MHCsTNF mice. Taken together, these observations suggest that sustained pro-inflammatory signaling in the adult heart is associated with a pro-fibrotic phenotype that arises, at least in part, from TGF-β mediated signaling, with resultant activation of Smad 2/3, leading to increased myocardial fibrosis and increased LV diastolic chamber stiffness.

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CTGF Expression is Induced by TGF- β in Cardiac Fibroblasts and Cardiac Myocytes: a Potential Role in Heart Fibrosis

Cited by 408 publications

References 30 publications

Angiotensin II Induces Connective Tissue Growth Factor Gene Expression via Calcineurin-Dependent Pathways

Angiotensin II Induces Connective Tissue Growth Factor Gene Expression via Calcineurin-Dependent Pathways

Defective Myofibroblast Formation from Mesenchymal Stem Cells in the Aging Murine Heart

Transforming growth factor-β receptor antagonism attenuates myocardial fibrosis in mice with cardiac-restricted overexpression of tumor necrosis factor

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