Upregulation of α8β1-integrin in cardiac fibroblast by angiotensin II and transforming growth factor-β1

2001 ◽  
Vol 281 (5) ◽  
pp. C1457-C1467 ◽  
Author(s):  
Gaétan Thibault ◽  
Marie-Josée Lacombe ◽  
Lynn M. Schnapp ◽  
Alexandre Lacasse ◽  
Fatiha Bouzeghrane ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Growth Factor ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Transforming Growth Factor Β1 ◽  
Cardiac Fibroblast ◽  
Extracellular Matrix Protein ◽  
Ang Ii ◽  
Tgf Β1

Using a novel pharmacological tool with125I-echistatin to detect integrins on the cell, we have observed that cardiac fibroblasts harbor five different RGD-binding integrins: α8β1, α3β1, α5β1, αvβ1, and αvβ3. Stimulation of cardiac fibroblasts by angiotensin II (ANG II) or transforming growth factor-β1 (TGF-β1) resulted in an increase of protein and heightening by 50% of the receptor density of α8β1-integrin. The effect of ANG II was blocked by an AT1, but not an AT2, receptor antagonist, or by an anti-TGF-β1 antibody. ANG II and TGF-β1 increased fibronectin secretion, smooth muscle α-actin synthesis, and formation of actin stress fibers and enhanced attachment of fibroblasts to a fibronectin matrix. The α8- and β1-subunits were colocalized by immunocytochemistry with vinculin or β3-integrin at focal adhesion sites. These results indicate that α8β1-integrin is an abundant integrin on rat cardiac fibroblasts. Its positive modulation by ANG II and TGF-β1 in a myofibroblast-like phenotype suggests the involvement of α8β1-integrin in extracellular matrix protein deposition and cardiac fibroblast adhesion.

Inhibiting albumin glycation attenuates dysregulation of VEGFR-1 and collagen IV subchain production and the development of renal insufficiency

2007 ◽  
Vol 292 (2) ◽  
pp. F789-F795 ◽  
Author(s):  
Margo P. Cohen ◽  
Gregory T. Lautenslager ◽  
Elizabeth Hud ◽  
Elizabeth Shea ◽  
Amy Wang ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Renal Insufficiency ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Glycated Albumin ◽  
Extracellular Matrix Protein ◽  
Type Iv ◽  
Endothelial Growth Factor ◽  
Tgf Β1

Glomerular cells in culture respond to albumin containing Amadori glucose adducts (the principal serum glycated protein), with activation of protein kinase C-β1, increased expression of transforming growth factor (TGF)-β1, the TGF-β type II signaling receptor, and the extracellular matrix proteins α1(IV) collagen and fibronectin and with decreased production of the podocyte protein nephrin. Decreasing the burden of glycated albumin in diabetic db/db mice significantly reduces glomerular overexpression of TGF-β1 mRNA, restores glomerular nephrin immunofluorescence, and lessens proteinuria, mesangial expansion, renal extracellular matrix protein production, and increased glomerular vascular endothelial growth factor (VEGF) immunostaining. In the present study, db/db mice were treated with a small molecule, designated 23CPPA, that inhibits the nonenzymatic condensation of glucose with the albumin protein to evaluate whether increased glycated albumin influences the production of VEGF receptors (VEGFRs) and type IV collagen subchains and ameliorates the development of renal insufficiency. Renal levels of VEGF and VEGFR-1 proteins and serum creatinine concentrations were significantly higher and renal levels of α3(IV) collagen and nephrin proteins and endogenous creatinine clearance values were significantly lower in control diabetic than in age-matched nondiabetic ( db/m) mice. These changes were significantly attenuated in db/db littermate mice treated from 9 to 18 wk of age with 23CPPA. The findings indicate that inhibiting excess nonenzymatic glycation of serum albumin improves renal molecular biology abnormalities and protects against the development of renal insufficiency in the db/db mouse.

Transforming growth factor-β1 induces cerebrovascular dysfunction and astrogliosis through angiotensin II type 1 receptor-mediated signaling pathways

2018 ◽  
Vol 96 (5) ◽  
pp. 527-534 ◽  
Author(s):  
Brice Ongali ◽  
Nektaria Nicolakakis ◽  
Xin-Kang Tong ◽  
Clotilde Lecrux ◽  
Hans Imboden ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Growth Factor ◽  
Signaling Pathways ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Cerebrovascular Reactivity ◽  
Cerebrovascular Dysfunction ◽  
Tgf Β1

Transgenic mice constitutively overexpressing the cytokine transforming growth factor-β1 (TGF-β1) (TGF mice) display cerebrovascular alterations as seen in Alzheimer’s disease (AD) and vascular cognitive impairment and dementia (VCID), but no or only subtle cognitive deficits. TGF-β1 may exert part of its deleterious effects through interactions with angiotensin II (AngII) type 1 receptor (AT1R) signaling pathways. We test such interactions in the brain and cerebral vessels of TGF mice by measuring cerebrovascular reactivity, levels of protein markers of vascular fibrosis, nitric oxide synthase activity, astrogliosis, and mnemonic performance in mice treated (6 months) with the AT1R blocker losartan (10 mg/kg per day) or the angiotensin converting enzyme inhibitor enalapril (3 mg/kg per day). Both treatments restored the severely impaired cerebrovascular reactivity to acetylcholine, calcitonin gene-related peptide, endothelin-1, and the baseline availability of nitric oxide in aged TGF mice. Losartan, but not enalapril, significantly reduced astrogliosis and cerebrovascular levels of profibrotic protein connective tissue growth factor while raising levels of antifibrotic enzyme matrix metallopeptidase-9. Memory was unaffected by aging and treatments. The results suggest a pivotal role for AngII in TGF-β1-induced cerebrovascular dysfunction and neuroinflammation through AT1R-mediated mechanisms. Further, they suggest that AngII blockers could be appropriate against vasculopathies and astrogliosis associated with AD and VCID.

scholarly journals Tanshinone IIA alters the transforming growth factor-β1/Smads pathway in angiotensin II-treated rat hepatic stellate cells

2020 ◽  
Vol 48 (6) ◽  
pp. 030006052092635
Author(s):  
Guo-wei Wei ◽  
Ke-yue Li ◽  
Ke-li Tang ◽  
Cheng-Xian Shi
Keyword(s):  
Angiotensin Ii ◽  
Growth Factor ◽  
Protein Expression ◽  
Hepatic Stellate Cells ◽  
Transforming Growth Factor ◽  
Stellate Cells ◽  
Transforming Growth Factor Β1 ◽  
Tanshinone Iia ◽  
Mrna And Protein Expression ◽  
Tgf Β1

Objective To investigate the effects of tanshinone IIA on the transforming growth factor-β1 (TGF-β1)/Smads signaling pathway in angiotensin II-treated hepatic stellate cells (HSCs). Methods HSCs were cultured and treated with angiotensin II (10 μM) or angiotensin II (10 μM) plus tanshinone IIA (3, 10, or 30 μM). Cells were incubated for 48 hours and proliferation was determined with the Cell Counting Kit-8. The relative mRNA expression of TGF-β1, Smad4, and Smad7 was measured by quantitative real-time PCR, and the relative protein expression levels were investigated by western blotting. Results After angiotensin II treatment, cell proliferation was significantly accelerated. Furthermore, both the mRNA and protein expression of TGF-β1 and Smad4 was significantly up-regulated, while the mRNA and protein expression of Smad7 was significantly down-regulated compared with the control cells. Tanshinone IIA inhibited the observed effects of angiotensin II in a concentration-dependent manner, with significant inhibition exerted by tanshinone IIA at 10 and 30 μM. Conclusions Angiotensin II promotes the proliferation of HSCs, possibly by regulating the expression of components along the TGF-β1/Smads signaling pathway. Tanshinone IIA inhibits the angiotensin II-induced activation of this pathway, and may, therefore, have preventive and therapeutic effects in liver fibrosis.

scholarly journals Enhanced Activity of Transforming Growth Factor β1 (TGF-β1) Bound to Cartilage Oligomeric Matrix Protein

2011 ◽  
Vol 286 (50) ◽  
pp. 43250-43258 ◽  
Author(s):  
Dominik R. Haudenschild ◽  
Eunmee Hong ◽  
Jasper H. N. Yik ◽  
Brett Chromy ◽  
Matthias Mörgelin ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cartilage Oligomeric Matrix Protein ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Enhanced Activity ◽  
Tgf Β1

scholarly journals Ac-SDKP inhibits transforming growth factor-β1-induced differentiation of human cardiac fibroblasts into myofibroblasts

2010 ◽  
Vol 298 (5) ◽  
pp. H1357-H1364 ◽  
Author(s):  
Hongmei Peng ◽  
Oscar A. Carretero ◽  
Edward L. Peterson ◽  
Nour-Eddine Rhaleb
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Transforming Growth Factor Β1 ◽  
Collagen Production ◽  
Smad7 Expression ◽  
Human Cardiac Fibroblasts ◽  
Tgf Β1

N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) inhibits collagen production and cell proliferation in cultured rat cardiac fibroblasts, but its effect on differentiation of fibroblasts into myofibroblasts is not known. High amounts of transforming growth factor-β1 (TGF-β1) have been found in fibrotic cardiac tissue. TGF-β1 converts fibroblasts into myofibroblasts, which produce more extracellular matrix proteins than fibroblasts. We hypothesized that 1) Ac-SDKP inhibits TGF-β1-induced differentiation of fibroblasts into myofibroblasts; and 2) this effect is mediated in part by blocking phosphorylation of small-mothers-against-decapentaplegic (Smad) 2 and extracellular signal-regulated kinase (ERK) 1/2. For this study, we used human fetal cardiac fibroblasts (HCFs), which do not spontaneously become myofibroblasts when cultured at low passages. We investigated the effect of Ac-SDKP on TGF-β1-induced HCF transformation into myofibroblasts, Smad2 and ERK1/2 phosphorylation, Smad7 expression, cell proliferation, and collagen production. We also investigated TGF-β1 production by HCFs stimulated with endothelin-1 (ET-1). As expected, HCFs treated with TGF-β1 transformed into myofibroblasts as indicated by increased expression of α-smooth muscle actin and a higher proportion of the embryonic isoform of smooth muscle myosin compared with untreated cells. TGF-β1 also increased Smad2 and ERK1/2 phosphorylation but did not affect Smad7 expression. In addition, TGF-β1 stimulated HCF proliferation as indicated by an increase in mitochondrial dehydrogenase activity and collagen production (hydroxyproline assay). Ac-SDKP significantly inhibited all of the effects of TGF-β1. It also inhibited ET-1-stimulated TGF-β1 production. We concluded that Ac-SDKP markedly suppresses differentiation of human cardiac fibroblasts into myofibroblasts, probably by inhibiting the TGF-β/Smad/ERK1/2 signaling pathway, and thus mediating its anti-fibrotic effects.

Abstract 11021: Circulating Cardiac Transforming Growth Factor-β is a Principal Determinant in Inducing Myocardial Hypertrophy in Transgenic Mice Overexpressing Exogenous Hepatic Transforming Growth Factor-β

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Shaukat A Khan ◽  
Takeshi Tsuda
Keyword(s):  
Growth Factor ◽  
Transgenic Mice ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Myocardial Hypertrophy ◽  
Cardiac Fibroblasts ◽  
Mrna Level ◽  
Transforming Growth Factor Β ◽  
Extracellular Matrix Protein ◽  
Potent Growth

Introduction: Transforming growth factor (TGF)-β is a potent growth factor that induces myocardial hypertrophy, but an interaction between circulating and myocardial TGF-β has been poorly understood. An extracellular matrix protein, fibulin-2, mediates exogenous TGF-β-induced endogenous TGF-β up-regulation in isolated cardiac fibroblasts. Hypothesis: Systemic TGF-β-induced myocardial hypertrophy is mediated primarily by enhanced myocardial TGF-β via paracrine fashion. Methods: We created double mutant mice with TGF-β1 over-expressing transgenic mice (TG) and fibulin-2 knockout mice (KO). TG developed myocardial hypertrophy due to excessive circulating hepatic TGF-β. We studied TGF-β dynamics between tissues and circulation during hypertrophic changes. Results: TG/WT developed significant myocardial hypertrophy at 8 weeks compared with non-TG (NTG) groups. Hypertrophy in TG/KO was significantly attenuated compared with TG/WT. Myocardial TGF-β mRNA level was significantly up-regulated in TG/WT compared with TG/KO or NGT groups, so was Smad2 activation, but myocardial TGF-β bioactivity was no different among all four groups. Serum carrier-bound TGF-β was significantly higher in TG/WT than in TG/KO or NTG groups, but free unbound TGF-β level was equally elevated in TG groups compared with NTG groups. Thus, hypertrophy in TG/WT may be attributed to increased serum carrier-bound TGF-β levels, not to either myocardial TGF-β activity or serum unbound TGF-β levels. Endogenous TGF-β mRNA level in kidney and liver was equally increased in TG group compared with NTG group, and was comparable in all 4 groups in lung, suggesting fibulin-2 was not involved in TGF-β-induced TGF-β synthesis in kidney, liver, or lung. Conclusions: Hepatic TGF-β-induced-myocardial TGF-β up-regulation was mediated by fibulin-2. In TG/WT, up-regulated myocardial TGF-β was mainly secreted into circulation as a soluble carrier-bound form and did not directly induce hypertrophy via paracrine fashion. It is this circulating endogenous myocardial TGF-β rather than transgene-induced hepatic TGF-β that is responsible for myocardial hypertrophy in TG/WT. Heart is a major endocrine organ in secreting circulating endogenous TGF-β in inducing myocardial hypertrophy.

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