Abstract 230: Cartilage Intermediate Layer Protein-1 Attenuates Pressure Overload-induced Cardiac Fibrosis by Targeting Transforming Growth Factor-β1

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Li Li ◽  
Cheng-Lin Zhang ◽  
Dan Wu ◽  
Li-Ling Wu
Keyword(s):  
Growth Factor ◽  
Intermediate Layer ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Pressure Overload ◽  
Transforming Growth Factor Β1 ◽  
Tgf Β1

Background: Cartilage intermediate layer protein-1 (CILP-1), a monomeric extracellular matrix glycoprotein expressed mainly in the middle zones of articular cartilage, interacts directly with transforming growth factor-β1 (TGF-β1). Recent studies showed that CILP-1 was upregulated in the heart tissue following cardiac ischemia reperfusion injury. However, the role of CILP-1 in pathological cardiac remodeling is poorly defined. Aims: To explore the effect of CILP-1 on myocardial interstitial fibrosis and reveal the possible molecular mechanism. Methods and Results: We found that CILP-1 was mainly expressed in mouse cardiac fibroblasts (CFs) by using western blot analysis and immunofluorescence. Myocardial expression of CILP-1 was upregulated in mice subjected to transverse aortic constriction (TAC) for 2, 4, and 8 weeks. AAV-9-mediated delivery of CILP-1 into mice increased the binding of CILP-1 with TGF-β1, attenuated interstitial fibrosis, and improved cardiac function. In cultured adult mouse CFs, CILP-1 overexpression inhibited myofibroblast differentiation and expression of profibrotic molecules induced by TGF-β1. Furthermore, CILP-1 attenuated TGF-β1-induced Smad3 phosphorylation and nuclear translocation. Conclusions: CILP-1 alleviates pressure overload-induced cardiac fibrosis and dysfunction. CILP-1 exerts its anti-fibrotic effect through targeting TGF-β1 signaling. This study will offer a new therapeutic strategy for preventing and treating myocardial interstitial remodeling.

scholarly journals Macrophage-specific deletion of transforming growth factor-β1 does not prevent renal fibrosis after severe ischemia-reperfusion or obstructive injury

2013 ◽  
Vol 305 (4) ◽  
pp. F477-F484 ◽  
Author(s):  
Sarah C. Huen ◽  
Gilbert W. Moeckel ◽  
Lloyd G. Cantley
Keyword(s):  
Growth Factor ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Transforming Growth Factor Β1 ◽  
Late Time ◽  
Tgf Β1

Macrophage infiltration is a prominent feature of the innate immune response to kidney injury. The persistence of macrophages is associated with tubulointerstitial fibrosis and progression of chronic kidney disease. Macrophages are known to be major producers of transforming growth factor-β1 (TGF-β1), especially in the setting of phagocytosis of apoptotic cells. TGF-β1 has long been implicated as a central mediator of tissue scarring and fibrosis in many organ disease models, including kidney disease. In this study, we show that homozygous deletion of Tgfb1 in myeloid lineage cells in mice heterozygous for Tgfb1 significantly reduces kidney Tgfb1 mRNA expression and Smad activation at late time points after renal ischemia-reperfusion injury. However, this reduction in kidney Tgfb1 expression and signaling results in only a modest reduction of isolated fibrosis markers and does not lead to decreased interstitial fibrosis in either ischemic or obstructive injury models. Thus, targeting macrophage-derived TGF-β1 does not appear to be an effective therapy for attenuating progressive renal fibrosis after kidney injury.

scholarly journals Smad7 Abrogates Transforming Growth Factor-β1-mediated Growth Inhibition in COLO-357 Cells through Functional Inactivation of the Retinoblastoma Protein

2005 ◽  
Vol 280 (23) ◽  
pp. 21858-21866 ◽  
Author(s):  
Nichole Boyer Arnold ◽  
Murray Korc
Keyword(s):  
Growth Factor ◽  
Growth Inhibition ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Retinoblastoma Protein ◽  
Transforming Growth Factor Β1 ◽  
Type I ◽  
Pancreatic Cancer Cells ◽  
Induced Apoptosis ◽  
Tgf Β1

Smad7 is overexpressed in 50% of human pancreatic cancers. COLO-357 pancreatic cancer cells engineered to overexpress Smad7 are resistant to the actions of transforming growth factor-β1 (TGF-β1) with respect to growth inhibition and cisplatin-induced apoptosis but not with respect to modulation of gene expression. To delineate the mechanisms underlying these divergent consequences of Smad7 overexpression, we studied the effects of Smad7 on TGF-β1-dependent signaling pathways and cell cycle regulating proteins. TGF-β1 induced the phosphorylation of MAPK, p38 MAPK, and AKT2 irrespective of the levels of Smad7, and inhibitors of these pathways did not alter TGF-β1 actions on cell growth. By contrast, Smad7 overexpression interfered with TGF-β1-mediated attenuation of cyclin A and B levels, inhibition of cdc2 dephosphorylation and CDK2 inactivation, up-regulation of p27, and the maintenance of the retinoblastoma protein (RB) in a hypophosphorylated state. Smad7 also suppressed TGF-β1-mediated inhibition of E2F activity but did not alter TGF-β1-mediated phosphorylation of Smad2, the nuclear translocation of Smad2/3/4, or DNA binding of the Smad2/3/4 complex. Although Smad7 did not associate with the type I TGF-β receptor (TβRI), SB-431542, an inhibitor of the kinase activity of this receptor, blocked TGF-β1-mediated effects on Smad-2 phosphorylation. These findings point toward a novel paradigm whereby Smad7 acts to functionally inactivate RB and de-repress E2F without blocking the activation of TβRI and the nuclear translocation of Smad2/3, thereby allowing for TGF-β1 to exert effects in a cancer cell that is resistant to TGF-β1-mediated growth inhibition.

scholarly journals Heterozygous knockout of transforming growth factor-β1 protects Dahl S rats against high salt-induced renal injury

2013 ◽  
Vol 45 (3) ◽  
pp. 110-118 ◽  
Author(s):  
Chun Cheng Andy Chen ◽  
Aron M. Geurts ◽  
Howard J. Jacob ◽  
Fan Fan ◽  
Richard J. Roman
Keyword(s):  
Blood Pressure ◽  
Growth Factor ◽  
Systolic Blood Pressure ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Transforming Growth Factor Β1 ◽  
High Salt ◽  
Glomerular Injury ◽  
Protein Excretion ◽  
Tgf Β1

The present study employed a zinc-finger nuclease strategy to create heterozygous knockout (KO) rats for the transforming growth factor-β1 ( Tgfb1) gene on the Dahl SS/Jr genetic background (TGF-β1+/− Dahl S). Intercrossing TGF-β1+/− rats did not produce any homozygous KO rats (66.4% +/−, 33.6% +/+), indicating that the mutation is embryonic lethal. Six-week-old wild-type (WT) littermates and TGF-β1+/− Dahl S rats were fed a 0.4% (low salt, LS) or 8% NaCl (high salt, HS) diet for 5 wk. Renal cortical expression of TGF-β1, urinary TGF-β1 excretion, proteinuria, glomerular injury and tubulointerstitial fibrosis, and systolic blood pressure were similar in WT and TGF-β1+/− Dahl S rats maintained on the LS diet. The expression and urinary excretion of TGF-β1 increased to a greater extent in WT than in TGF-β1+/−Dahl S rats fed an HS diet for 1 wk. Systolic blood pressure rose by the same extent to 235 ± 2 mmHg in WT and 239 ± 4 mmHg in TGF-β1+/− Dahl S rats fed a HS diet for 5 wk. However, urinary protein excretion was significantly lower in TGF-β1+/− Dahl S than in the WT animals. The degree of glomerular injury and renal cortical and outer medullary fibrosis was markedly less in TGF-β1+/− than in WT rats. These findings suggest that the loss of one copy of the TGF-β1 gene blunts the increase in renal TGF-β1 protein expression and slows the progression of proteinuria, glomerulosclerosis, and renal interstitial fibrosis in Dahl S rats fed an HS diet independently of changes in blood pressure.

scholarly journals Aberrant Transforming Growth Factor β1 Signaling and SMAD4 Nuclear Translocation Confer Epigenetic Repression of ADAM19 in Ovarian Cancer

Neoplasia ◽  
2008 ◽  
Vol 10 (9) ◽  
pp. 908-IN2 ◽  
Author(s):  
Michael W.Y. Chan ◽  
Yi-Wen Huang ◽  
Corinna Hartman-Frey ◽  
Chieh-Ti Kuo ◽  
Daniel Deatherage ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Transforming Growth Factor Β1 ◽  
Epigenetic Repression

scholarly journals JNK and p38 Inhibitors Prevent Transforming Growth Factor-β1-Induced Myofibroblast Transdifferentiation in Human Graves’ Orbital Fibroblasts

2021 ◽  
Vol 22 (6) ◽  
pp. 2952
Author(s):  
Tzu-Yu Hou ◽  
Shi-Bei Wu ◽  
Hui-Chuan Kau ◽  
Chieh-Chih Tsai
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Mapk Pathway ◽  
Transforming Growth Factor Β1 ◽  
Tissue Growth ◽  
Mitogen Activated Protein Kinase ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Western Blots ◽  
Orbital Fibroblasts ◽  
Tgf Β1

Transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation from orbital fibroblasts is known to dominate tissue remodeling and fibrosis in Graves’ ophthalmopathy (GO). However, the signaling pathways through which TGF-β1 activates Graves’ orbital fibroblasts remain unclear. This study investigated the role of the mitogen-activated protein kinase (MAPK) pathway in TGF-β1-induced myofibroblast transdifferentiation in human Graves’ orbital fibroblasts. The MAPK pathway was assessed by measuring the phosphorylation of p38, c-Jun N-terminal kinase (JNK), and extracellular-signal-regulated kinase (ERK) by Western blots. The expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and fibronectin representing fibrogenesis was estimated. The activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) responsible for extracellular matrix (ECM) metabolism were analyzed. Specific pharmacologic kinase inhibitors were used to confirm the involvement of the MAPK pathway. After treatment with TGF-β1, the phosphorylation levels of p38 and JNK, but not ERK, were increased. CTGF, α-SMA, and fibronectin, as well as TIMP-1 and TIMP-3, were upregulated, whereas the activities of MMP-2/-9 were inhibited. The effects of TGF-β1 on the expression of these factors were eliminated by p38 and JNK inhibitors. The results suggested that TGF-β1 could induce myofibroblast transdifferentiation in human Graves’ orbital fibroblasts through the p38 and JNK pathways.

scholarly journals Transforming growth factor-β1-induced N-cadherin drives cell–cell communication through connexin43 in osteoblast lineage

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Yueyi Yang ◽  
Wenjing Liu ◽  
JieYa Wei ◽  
Yujia Cui ◽  
Demao Zhang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Gap Junction ◽  
Cell Line ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Cx43 Expression ◽  
Mc3t3 Cell ◽  
Primary Osteoblasts ◽  
Tgf Β1 ◽  
Cell Cell

AbstractGap junction (GJ) has been indicated to have an intimate correlation with adhesion junction. However, the direct interaction between them partially remains elusive. In the current study, we aimed to elucidate the role of N-cadherin, one of the core components in adhesion junction, in mediating connexin 43, one of the functional constituents in gap junction, via transforming growth factor-β1(TGF-β1) induction in osteoblasts. We first elucidated the expressions of N-cadherin induced by TGF-β1 and also confirmed the upregulation of Cx43, and the enhancement of functional gap junctional intercellular communication (GJIC) triggered by TGF-β1 in both primary osteoblasts and MC3T3 cell line. Colocalization analysis and Co-IP experimentation showed that N-cadherin interacts with Cx43 at the site of cell–cell contact. Knockdown of N-cadherin by siRNA interference decreased the Cx43 expression and abolished the promoting effect of TGF-β1 on Cx43. Functional GJICs in living primary osteoblasts and MC3T3 cell line were also reduced. TGF-β1-induced increase in N-cadherin and Cx43 was via Smad3 activation, whereas knockdown of Smad3 signaling by using siRNA decreased the expressions of both N-cadherin and Cx43. Overall, these data indicate the direct interactions between N-cadherin and Cx43, and reveal the intervention of adhesion junction in functional gap junction in living osteoblasts.

Sign in / Sign up

Export Citation Format

Share Document