Apigenin suppresses TGF-β1-induced cardiac fibroblast differentiation and collagen synthesis through the downregulation of HIF-1α expression by miR-122-5p

Phytomedicine ◽  
2021 ◽  
Vol 83 ◽  
pp. 153481
Author(s):  
Wang Feng ◽  
Zhao Ying ◽  
Fan Ke ◽  
Xie Mei-Lin
Keyword(s):  
Collagen Synthesis ◽  
Cardiac Fibroblast ◽  
Tgf Β1

Hexarelin suppresses cardiac fibroblast proliferation and collagen synthesis in rat

2007 ◽  
Vol 293 (5) ◽  
pp. H2952-H2958 ◽  
Author(s):  
Xiangbin Xu ◽  
Jinjiang Pang ◽  
Hongchao Yin ◽  
Meixiu Li ◽  
Wei Hao ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Collagen Synthesis ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Cardiac Fibroblast ◽  
Ang Ii ◽  
Fibroblast Proliferation ◽  
Growth Hormone Secretagogue ◽  
Tgf Β1

Abnormal growth of cardiac fibroblasts is critically involved in the pathophysiology of cardiac hypertrophy/remodeling. Hexarelin is a synthetic growth hormone secretagogue (GHS), which possesses a variety of cardiovascular protective activities mediated via the GHS receptor (GHSR), including improving cardiac dysfunction and remodeling. The cellular and molecular mechanisms underlying the effect of GHS on cardiac fibrosis are, however, not clear. In this report, cultured cardiac fibroblasts from 8-day-old rats were stimulated with ANG II or FCS to induce proliferation. The fibroblast proliferation and DNA and collagen synthesis were evaluated utilizing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, 3H-thymidine incorporation, and 3H-proline incorporation. The level of mRNA of transforming growth factor (TGF)-β was evaluated by RT-PCR, and the active TGF-β1 release from cardiac fibroblasts was evaluated by ELISA. The level of cellular cAMP was measured by radioimmunoassay. In addition, the effects of 3,7-dimethyl-l-propargylxanthine (DMPX; a specific adenosine receptor A2R antagonist) and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; a specific A1R antagonist) were tested. It was found that incubation with 10−7 mol/l hexarelin for 24 h 1) inhibited the ANG II-induced proliferation and collagen synthesis and the 5% FCS- and TGF-β-induced increase of DNA synthesis in cardiac fibroblast and 2) reduced ANG II-induced upregulation of TGF-β mRNA expression and active TGF-β1 release from fibroblasts. Hexarelin increased the cellular level of cAMP in cardiac fibroblasts. DMPX (10−8 mol/l) but not DPCPX abolished the effect of hexarelin on cardiac fibroblast DNA synthesis. It is concluded that hexarelin inhibits DNA and collagen synthesis and proliferation of cardiac fibroblasts through activation of both GHSR and A2R and diminishment of ANG II-induced increase in TGF-β expression and release.

scholarly journals Notch Signaling May Negatively Regulate Neonatal Rat Cardiac Fibroblast-Myofibroblast Transformation

2011 ◽  
pp. 739-748 ◽  
Author(s):  
Y.-H. FAN ◽  
H. DONG ◽  
Q. PAN ◽  
Y.-J. CAO ◽  
H. LI ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Myocardial Fibrosis ◽  
Collagen Synthesis ◽  
Butyl Ester ◽  
Cardiac Fibroblast ◽  
Notch Receptor ◽  
Neonatal Rat ◽  
Dependent Manner ◽  
Notch Receptors ◽  
Tgf Β1

Cardiac fibroblast-myofibroblast transformation (CMT) is a critical event in the initiation of myocardial fibrosis. Notch signaling has been shown to regulate myofibroblast transformation from other kinds of cells. However, whether Notch signaling is also involved in CMT remains unclear. In the present study, expressions of Notch receptors in cardiac fibroblasts (CFs) were examined, effects of Notch signaling inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) and transforming growth factor-β1 (TGF-β1) on CMT were determined by increasing alpha-smooth muscle actin (α-SMA) expression and collagen synthesis, and Notch signaling was examined by analyzing expressions of Notch receptors. The results showed that: (1) Notch receptor 1, 2, 3 and 4 were all expressed in CFs; (2) DAPT promoted CMT in a time-dependent manner; (3) During the period of CMT induced by TGF-β1, expressions of Notch receptor 1, 3 and 4 in CFs were down-regulated, whereas there was no change for Notch receptor 2. Moreover, the downtrends of Notch 1, 3 and 4 were corresponding to the trend growth of α-SMA expression and collagen synthesis. These results suggested that inhibiting of Notch signaling might promote CMT. The down-regulations of Notch receptor 1, 3 and 4 induced by TGF-β1 may facilitate CMT. In conclusion, inhibition of Notch signaling might be a novel mechanism of CMT in myocardial fibrosis.

Urotensin-2 promotes collagen synthesis via ERK1/2-dependent and ERK1/2-independent TGF-β1 in neonatal cardiac fibroblasts

2011 ◽  
Vol 35 (2) ◽  
pp. 93-98 ◽  
Author(s):  
Hong‑Yan Dai ◽  
Tao He ◽  
Xiao‑Lu Li ◽  
Wen‑Liang Xu ◽  
Zhi‑Ming Ge
Keyword(s):  
Collagen Synthesis ◽  
Cardiac Fibroblasts ◽  
Tgf Β1

Abstract 15392: Inflammation and Ischemic Heart Failure: Monocyte-Mediated Cardiac Fibroblast Activation and Matrix Remodeling Through a Direct Cell-Cell Contact Mechanism

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Holly E Mewhort ◽  
Brodie D Lipon ◽  
Daniyil A Svystonyuk ◽  
David G Guzzardi ◽  
Paul W Fedak
Keyword(s):  
Peripheral Blood ◽  
Cardiac Fibroblast ◽  
Cell Contact ◽  
Β1 Integrin ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes ◽  
Fibroblast Activation ◽  
Direct Cell ◽  
Tgf Β1 ◽  
Cell Cell

BACKGROUND: Following myocardial infarction (MI), activated cardiac myofibroblasts facilitate extracellular matrix (ECM) remodeling to prevent mechanical complications. However, prolonged myofibroblast activity leads to dysregulation of the ECM, maladaptive remodeling, fibrosis and heart failure (HF). Chronic inflammation is believed to drive persistent myofibroblast activity, however, the mechanisms are unclear. In this study, we explored the effects of peripheral blood monocytes on human cardiac fibroblast activation in a 3D ECM microenvironment. METHODS/RESULTS: Human cardiac fibroblasts isolated from surgical human heart biopsies were seeded into 3D collagen matrices. Peripheral blood monocytes isolated from healthy human donors were co-cultured with fibroblasts. Monocytes increased fibroblast activation measured by collagen ECM contraction (17.9±11.1% increase; p<0.01) and resulted in local ECM remodeling observed by confocal microscopy. Under co-culture conditions that prevent cell-cell contact but allow interaction via paracrine factors, monocytes had minimal effects on fibroblast activation (6.4±7.0 vs.17.9±11.1% increase, respectively; p<0.01). Multiplex analysis of the co-culture media revealed an increase in the paracrine factors Transforming Growth Factor-beta 1 (TGF-β1) and Matrix Metalloproteinase 9 when monocytes and fibroblasts were cultured under cell-cell contact conditions (162.2±11.7pg/mL and 17.5±0.5ng/mL, respectively, vs. 21.8±5.7pg/mL and 4.9 ±0.4ng/mL; p<0.001). TGF-β1 blockade abolished monocyte induced cardiac fibroblast activation, as did β1-integrin. These data suggest direct cell-cell interaction between monocytes and cardiac fibroblasts through β1-integrin results in TGF-β1 release facilitating fibroblast activation and matrix remodeling. CONCLUSION: For the first time, we demonstrate that peripheral blood monocytes stimulate human cardiac fibroblast activation through a mechanism involving TGF-β1 release as a consequence of direct cell-cell interaction through β1-integrin. These data implicate inflammation as a driver of cardiac fibrosis post-MI, highlighting potential novel therapeutic targets for the treatment of ischemic HF.

scholarly journals Soluble St2 Induces Cardiac Fibroblast Activation and Collagen Synthesis via Neuropilin-1

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1667 ◽  
Author(s):  
Lara Matilla ◽  
Vanessa Arrieta ◽  
Eva Jover ◽  
Amaia Garcia-Peña ◽  
Ernesto Martinez-Martinez ◽  
...  
Keyword(s):  
Collagen Synthesis ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Interleukin 1 ◽  
Cardiac Fibroblast ◽  
Pathogenic Role ◽  
Fibroblast Activation ◽  
Neuropilin 1 ◽  
Human Cardiac Fibroblasts

Circulating levels of soluble interleukin 1 receptor-like 1 (sST2) are increased in heart failure and associated with poor outcome, likely because of the activation of inflammation and fibrosis. We investigated the pathogenic role of sST2 as an inductor of cardiac fibroblasts activation and collagen synthesis. The effects of sST2 on human cardiac fibroblasts was assessed using proteomics and immunodetection approaches to evidence the upregulation of neuropilin-1 (NRP-1), a regulator of the profibrotic transforming growth factor (TGF)-β1. In parallel, sST2 increased fibroblast activation, collagen and fibrosis mediators. Pharmacological inhibition of nuclear factor-kappa B (NF-κB) restored NRP-1 levels and blocked profibrotic effects induced by sST2. In NRP-1 knockdown cells, sST2 failed to induce fibroblast activation and collagen synthesis. Exogenous NRP-1 enhanced cardiac fibroblast activation and collagen synthesis via NF-κB. In a pressure overload rat model, sST2 was elevated in association with cardiac fibrosis and was positively correlated with NRP-1 expression. Our study shows that sST2 induces human cardiac fibroblasts activation, as well as the synthesis of collagen and profibrotic molecules. These effects are mediated by NRP-1. The blockade of NF-κB restored NRP-1 expression, improving the profibrotic status induced by sST2. These results show a new pathogenic role for sST2 and its mediator, NRP-1, as cardiac fibroblast activators contributing to cardiac fibrosis.

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.

scholarly journals MicroRNA‐497 elevation or LRG1 knockdown promotes osteoblast proliferation and collagen synthesis in osteoporosis via TGF‐β1/Smads signalling pathway

2020 ◽  
Vol 24 (21) ◽  
pp. 12619-12632
Author(s):  
ZhengTao Gu ◽  
DengHui Xie ◽  
CaiQiang Huang ◽  
Rui Ding ◽  
RongKai Zhang ◽  
...  
Keyword(s):  
Collagen Synthesis ◽  
Signalling Pathway ◽  
Osteoblast Proliferation ◽  
Tgf Β1

scholarly journals The MicroRNA miR-155 Is Essential in Fibrosis

2019 ◽  
Vol 5 (1) ◽  
pp. 23 ◽  
Author(s):  
Mousa Eissa ◽  
Carol Artlett
Keyword(s):  
Collagen Synthesis ◽  
Regulation Of Gene Expression ◽  
Viable Option ◽  
Adaptive Immune ◽  
Biological Interest ◽  
Integral Role ◽  
Fibrotic Disorders ◽  
Adaptive Immune Systems ◽  
Tgf Β1

The function of microRNAs (miRNAs) during fibrosis and the downstream regulation of gene expression by these miRNAs have become of great biological interest. miR-155 is consistently upregulated in fibrotic disorders, and its ablation downregulates collagen synthesis. Studies demonstrate the integral role of miR-155 in fibrosis, as it mediates TGF-β1 signaling to drive collagen synthesis. In this review, we summarize recent findings on the association between miR-155 and fibrotic disorders. We discuss the cross-signaling between macrophages and fibroblasts that orchestrates the upregulation of collagen synthesis mediated by miR-155. As miR-155 is involved in the activation of the innate and adaptive immune systems, specific targeting of miR-155 in pathologic cells that make excessive collagen could be a viable option before the depletion of miR-155 becomes an attractive antifibrotic approach.

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