scholarly journals Neferine inhibits proliferation and collagen synthesis induced by high glucose in cardiac fibroblasts and reduces cardiac fibrosis in diabetic mice

Oncotarget ◽  
2016 ◽  
Vol 7 (38) ◽  
pp. 61703-61715 ◽  
Author(s):  
Xue Liu ◽  
Xiuhui Song ◽  
Jianjun Lu ◽  
Xueying Chen ◽  
Ershun Liang ◽  
...  
Keyword(s):  
High Glucose ◽  
Collagen Synthesis ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Diabetic Mice

scholarly journals Cafestol Inhibits High-Glucose-Induced Cardiac Fibrosis in Cardiac Fibroblasts and Type 1-Like Diabetic Rats

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Ju-Chi Liu ◽  
Po-Yuan Chen ◽  
Wen-Rui Hao ◽  
Yi-Chung Liu ◽  
Ping-Chiang Lyu ◽  
...  
Keyword(s):  
High Glucose ◽  
Collagen Synthesis ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Biological Effects ◽  
Diabetic Rats ◽  
Enzyme Linked Immunosorbent Assay ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Tgf Β1

Diabetes is associated with the development of myocardial fibrosis, which is related to various cardiac diseases. Cafestol, one of the active ingredients in coffee, has been reported to exert biological effects. However, whether cafestol can ameliorate diabetes-induced cardiac fibrosis remains unknown. The aim of this study was to evaluate the effects of cafestol on cardiac fibrosis in high-glucose-treated cardiac fibroblasts and streptozocin- (STZ-) induced diabetic rats. Rat cardiac fibroblasts were cultured in high-glucose (25 mM) media in the absence or presence of cafestol, and the changes in collagen synthesis, transforming growth factor-β1 (TGF-β1) production, and related signaling molecules were assessed on the basis of 3H-proline incorporation, enzyme-linked immunosorbent assay, and western blotting. Cardiac fibroblasts exposed to high-glucose conditions exhibited increased collagen synthesis, TGF-β1 production, and Smad2/3 phosphorylation, and these effects were mitigated by cafestol treatment. Furthermore, cafestol increased the translocation of nuclear factor erythroid 2-related factor 2 and increased the expression of heme oxygenase-1. The results of molecular docking analysis suggested a selective interaction of cafestol with Kelch-like ECH-associated protein 1. The rats with untreated STZ-induced diabetes exhibited considerable collagen accumulation, which was ameliorated by cafestol. Moreover, activities of catalase, superoxide dismutase, general matrix metalloproteinase, and reduced glutathione concentration were upregulated, whereas malondialdehyde level was downregulated by treatment with cafestol in rats with cardiac fibrosis. These findings highlight the effects of cafestol, which may be useful in treating diabetes-related cardiac fibrosis.

scholarly journals Tanshinone IIA Inhibits High Glucose-Induced Collagen Synthesis via Nuclear Factor Erythroid 2-Related Factor 2 in Cardiac Fibroblasts

2018 ◽  
Vol 51 (5) ◽  
pp. 2250-2261 ◽  
Author(s):  
Yi-Ting  Tsai ◽  
Shih-Hurng Loh ◽  
Chung-Yi Lee ◽  
Shiao-Ping Lee ◽  
Yen-Lin Chen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
High Glucose ◽  
Collagen Synthesis ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Tanshinone Iia ◽  
Enzyme Linked Immunosorbent Assay ◽  
Related Factor ◽  
Nuclear Factor ◽  
Tgf Β1

Background/Aims: Diabetes is associated with increased incidence of myocardial dysfunction, which is partly characterized by interstitial and perivascular fibrosis. Cardiac fibroblasts have been identified as an important participant in the development of cardiac fibrosis. Exposure of cultured cardiac fibroblasts to high glucose resulted in increased collagen synthesis. Tanshinone IIA can alleviate the ventricular fibrosis that develops in a number of different experimental conditions. However, whether tanshinone IIA can prevent high glucose-induced collagen synthesis in cardiac fibroblasts remains unknown. The aim of this study was to evaluate the effects of tanshinone IIA on high glucose-induced collagen synthesis in cardiac fibroblasts. Methods: Rat cardiac fibroblasts were cultured in high glucose (25 mM) media in the absence or presence of tanshinone IIA and the changes in collagen synthesis, transforming growth factor-β1 (TGF-β1) production and related signaling molecules were assessed by 3H-proline incorporation, quantitative polymerase chain reaction, enzyme linked immunosorbent assay, and Western blotting. Results: The results indicate cardiac fibroblasts exposed to high glucose condition show increased cell proliferation and collagen synthesis and these effects were abolished by tanshinone IIA treatment. Furthermore, the inhibitory effect of tanshinone IIA on high glucose induced cell proliferation and collagen synthesis may be associated with its activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) and the inhibition of TGF-β1 production and Smad2/3 phosphorylation. Conclusion: In summary, our results highlights the critical role tanshinone IIA plays as an antioxidant in attenuating high glucose-mediated collagen synthesis through inhibiting TGF-β1/Smad signaling in cardiac fibroblasts which provide a mechanistic basis for the clinical application of tanshinone IIA in the treating diabetic-related cardiac fibrosis.

scholarly journals Role for high-glucose-induced protein O-GlcNAcylation in stimulating cardiac fibroblast collagen synthesis

2014 ◽  
Vol 306 (9) ◽  
pp. C794-C804 ◽  
Author(s):  
Hugo Aguilar ◽  
Eduardo Fricovsky ◽  
Sang Ihm ◽  
Magdalena Schimke ◽  
Lisandro Maya-Ramos ◽  
...  
Keyword(s):  
High Glucose ◽  
Collagen Synthesis ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Transforming Growth Factor Β1 ◽  
Protein Levels ◽  
Normal Glucose ◽  
Arginase Ii ◽  
Tgf Β1

Excess enzyme-mediated protein O-GlcNAcylation is known to occur with diabetes mellitus. A characteristic of diabetic cardiomyopathy is the development of myocardial fibrosis. The role that enhanced protein O-GlcNAcylation plays in modulating the phenotype of cardiac fibroblasts (CF) is unknown. To address this issue, rat CF were cultured in normal glucose (NG; 5 mM glucose) or high-glucose (HG; 25 mM) media for 48 h. Results demonstrate that CF cultured in HG have higher levels (∼50%) of overall protein O-GlcNAcylation vs. NG cells. Key regulators of collagen synthesis such as transforming-growth factor-β1 (TGF-β1), SMADs 2/3, and SMAD 7 protein levels, including those of arginase I and II, were altered, leading to increases in collagen levels. The nuclear transcription factor Sp1 and arginase II evidence excess O-GlcNAcylation in HG cells. Expression in CF of an adenovirus coding for the enzyme N-acetylglucosaminidase, which removes O-GlcNAc moieties from proteins, decreased Sp1 and arginase II O-GlcNAcylation and restored HG-induced perturbations in CF back to NG levels. These findings may have important pathophysiological implications for the development of diabetes-induced cardiac fibrosis.

scholarly journals Inhibitory Effects of Momordicine I on High-Glucose-Induced Cell Proliferation and Collagen Synthesis in Rat Cardiac Fibroblasts

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Po-Yuan Chen ◽  
Neng-Lang Shih ◽  
Wen-Rui Hao ◽  
Chun-Chao Chen ◽  
Ju-Chi Liu ◽  
...  
Keyword(s):  
High Glucose ◽  
Collagen Synthesis ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Critical Role ◽  
Inhibitory Effect ◽  
Related Factor ◽  
Fibroblast Proliferation ◽  
Fibroblast Activation

Diabetes-associated cardiac fibrosis is a severe cardiovascular complication. Momordicine I, a bioactive triterpenoid isolated from bitter melon, has been demonstrated to have antidiabetic properties. This study investigated the effects of momordicine I on high-glucose-induced cardiac fibroblast activation. Rat cardiac fibroblasts were cultured in a high-glucose (25 mM) medium in the absence or presence of momordicine I, and the changes in collagen synthesis, transforming growth factor-β1 (TGF-β1) production, and related signaling molecules were assessed. Increased oxidative stress plays a critical role in the development of high-glucose-induced cardiac fibrosis; we further explored momordicine I’s antioxidant activity and its effect on fibroblasts. Our data revealed that a high-glucose condition promoted fibroblast proliferation and collagen synthesis and these effects were abolished by momordicine I (0.3 and 1 μM) pretreatment. Furthermore, the inhibitory effect of momordicine I on high-glucose-induced fibroblast activation may be associated with its activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the inhibition of reactive oxygen species formation, TGF-β1 production, and Smad2/3 phosphorylation. The addition of brusatol (a selective inhibitor of Nrf2) or Nrf2 siRNA significantly abolished the inhibitory effect of momordicine I on fibroblast activation. Our findings revealed that the antifibrotic effect of momordicine I was mediated, at least partially, by the inhibition of the TGF-β1/Smad pathway, fibroblast proliferation, and collagen synthesis through Nrf2 activation. Thus, this work provides crucial insights into the molecular pathways for the clinical application of momordicine I for treating diabetes-associated cardiac fibrosis.

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.

scholarly journals The Diabetic Cardiac Fibroblast: Mechanisms Underlying Phenotype and Function

2020 ◽  
Vol 21 (3) ◽  
pp. 970 ◽  
Author(s):  
Scott P. Levick ◽  
Alexander Widiapradja
Keyword(s):  
High Glucose ◽  
Effector Cell ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Cardiac Fibroblast ◽  
Review Article ◽  
Cardiomyocyte Hypertrophy ◽  
Preserved Ejection Fraction ◽  
Microvascular Damage ◽  
And Function

Diabetic cardiomyopathy involves remodeling of the heart in response to diabetes that includes microvascular damage, cardiomyocyte hypertrophy, and cardiac fibrosis. Cardiac fibrosis is a major contributor to diastolic dysfunction that can ultimately result in heart failure with preserved ejection fraction. Cardiac fibroblasts are the final effector cell in the process of cardiac fibrosis. This review article aims to describe the cardiac fibroblast phenotype in response to high-glucose conditions that mimic the diabetic state, as well as to explain the pathways underlying this phenotype. As such, this review focuses on studies conducted on isolated cardiac fibroblasts. We also describe molecules that appear to oppose the pro-fibrotic actions of high glucose on cardiac fibroblasts. This represents a major gap in knowledge in the field that needs to be addressed.

scholarly journals Antifibrotic cardioprotection of berberine via downregulating myocardial IGF-1 receptor-regulated MMP-2/MMP-9 expression in diabetic rats

2018 ◽  
Vol 315 (4) ◽  
pp. H802-H813 ◽  
Author(s):  
Guohua Li ◽  
Wenjuan Xing ◽  
Min Zhang ◽  
Fenghao Geng ◽  
Hongyan Yang ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
High Glucose ◽  
Cardiac Fibrosis ◽  
Collagen Type ◽  
Cardiac Fibroblasts ◽  
Collagen Type I ◽  
Diabetic Rats ◽  
Type I ◽  
Antifibrotic Effect

Diabetic cardiac fibrosis increases ventricular stiffness and facilitates the occurrence of diastolic dysfunction. Our previous studies have shown that berberine, a natural alkaloid, attenuates cardiac ischemia-reperfusion injury in diabetic rats. The aim of present study was to investigate the effects of long-term berberine treatment on cardiac remodeling in diabetic rats and the underlying mechanisms. Diabetic rats induced by low-dose streptozotocin injection combined with 8 wk of high-fat diet displayed significant cardiac matrix collagen deposition and dysfunction, whereas berberine administration (200 mg·kg−1·day−1, gavage 4 wk) significantly ameliorated cardiac fibrosis and dysfunction and reduced cardiac IGF-1 receptor (IGF-1R) expression in diabetic rats. Interestingly, IGF-1R expression was upregulated in cardiac fibroblasts isolated from diabetic hearts or cultured in high-glucose conditions (30 mM). High glucose treatment or IGF-1R overexpression increased matrix metalloproteinase (MMP)-2/MMP-9 expression, α-smooth muscle actin (α-SMA), and collagen type I expression in cardiac fibroblasts. In contrast, berberine treatment significantly inhibited IGF-1R expression and exerted an antifibrotic effect in high glucose-cultured cardiac fibroblasts, as manifested by decreased MMP-2/MMP-9, α-SMA, and collagen type I expression, whereas IGF-1R siRNA plus berberine treatment did not further enhance this antifibrotic effect compared with berberine treatment alone. Taken together, long-term berberine treatment ameliorates cardiac fibrosis and dysfunction by downregulating IGF-1R expression in cardiac fibroblasts and subsequently reducing MMP-2/MMP-9, α-SMA, and collagen type I expression in diabetic hearts. The findings suggest the therapeutic potential of berberine for diabetic cardiomyopathy associated with cardiac fibrosis. NEW & NOTEWORTHY Berberine downregulated IGF-1 receptor expression and matrix metalloproteinase-2/matrix metalloproteinase-9 levels in cardiac fibroblasts and thus inhibited fibroblast differentiation and collagen overproduction in diabetic hearts, suggesting a novel mechanism for antifibrotic cardioprotection of berberine in type 2 diabetes.

Fasudil hydrochloride hydrate, a Rho-kinase inhibitor, suppresses high glucose-induced proliferation and collagen synthesis in rat cardiac fibroblasts

2011 ◽  
Vol 38 (6) ◽  
pp. 387-394 ◽  
Author(s):  
Hong Zhou ◽  
Kai-Xia Zhang ◽  
Yong-Jun Li ◽  
Bing-Yan Guo ◽  
Mei Wang ◽  
...  
Keyword(s):  
High Glucose ◽  
Collagen Synthesis ◽  
Kinase Inhibitor ◽  
Cardiac Fibroblasts ◽  
Rho Kinase ◽  
Rho Kinase Inhibitor

scholarly journals High Glucose Activated Cardiac Fibroblasts by a Disruption of Mitochondria-Associated Membranes

2021 ◽  
Vol 12 ◽  
Author(s):  
Ling-Yu Zhang ◽  
Rui-Ting Lin ◽  
Hao-Ran Chen ◽  
Yong-Cong Yang ◽  
Meng-Fei Lin ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mitochondrial Respiration ◽  
High Glucose ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Underlying Mechanism ◽  
Luciferase Reporter ◽  
Mitofusin 2 ◽  
Atp Production ◽  
Proliferation And Apoptosis

Cardiac fibrosis is evident even in the situation without a significant cardiomyocyte loss in diabetic cardiomyopathy and a high glucose (HG) level independently activates the cardiac fibroblasts (CFs) and promotes cell proliferation. Mitochondrial respiration and glycolysis, which are key for cell proliferation and the mitochondria-associated membranes (MAMs), are critically involved in this process. However, the roles and the underlying mechanism of MAMs in the proliferation of HG-induced CFs are largely unknown. The proliferation and apoptosis of CFs responding to HG treatment were evaluated. The MAMs were quantified, and the mitochondrial respiration and cellular glycolytic levels were determined using the Seahorse XF analyzer. The changes of signal transducer and activator of transcription 3 (STAT3) and mitofusin-2 (MFN2) in responding to HG were also determined, the effects of which on cell proliferation, MAMs, and mitochondrial respiration were assessed. The effects of STAT3 on MFN2 transcription was determined by the dual-luciferase reporter assay (DLRA) and chromatin immunoprecipitation (CHIP). HG-induced CFs proliferation increased the glycolytic levels and adenosine triphosphate (ATP) production, while mitochondrial respiration was inhibited. The MAMs and MFN2 expressions were significantly reduced on the HG treatment, and the restoration of MFN2 expression counteracted the effects of HG on cell proliferation, mitochondrial respiration of the MAMs, glycolytic levels, and ATP production. The mitochondrial STAT3 contents were not changed by HG, but the levels of phosphorylated STAT3 and nuclear STAT3 were increased. The inhibition of STAT3 reversed the reduction of MFN2 levels induced by HG. The DLRA and CHIP directly demonstrated the negative regulation of MFN2 by STAT3 at the transcription levels via interacting with the sequences in the MFN2 promoter region locating at about −400 bp counting from the start site of transcription. The present study demonstrated that the HG independently induced CFs proliferation via promoting STAT3 translocation to the nucleus, which switched the mitochondrial respiration to glycolysis to produce ATP by inhibiting MAMs in an MFN2-depression manner.

Abstract 13917: Inhibition of GRK2 Prevents Cardiac Fibroblast-Mediated Maladaptive Ventricular Remodeling

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Jennifer L Philip ◽  
Xianyao Xu ◽  
Mei Han ◽  
Jinju Li ◽  
Abdur Razzaque ◽  
...  
Keyword(s):  
Collagen Synthesis ◽  
Cardiac Fibrosis ◽  
Ventricular Remodeling ◽  
Cardiac Fibroblasts ◽  
Male Rats ◽  
Lv Function ◽  
Intracellular Camp ◽  
Adenoviral Delivery ◽  
Fractional Shortening

Remote (non-infarct) territory fibrosis is a significant cause of post-myocardial infarction (MI) heart failure (HF). We have previously shown that increased activity of G protein-coupled receptor kinase-2 (GRK2) in adult human cardiac fibroblasts (CF) isolated from failing hearts is an important mechanism of cardiac fibrosis. This study investigates the potential therapeutic role of GRK2 inhibition on CF biology in vivo. Adult male rats underwent LAD ligation to induce post-MI HF. GRK2 was inhibited by intra-coronary adenoviral-mediated delivery of a GRK2 inhibitor (Ad-GRK2ct) immediately following LAD ligation (n=11). Control rats received a null adenovirus (n=10). Animals were studied prior to and up to 12 weeks (wks) post-MI and adenoviral delivery. There was a significant decline in LV function at 2 wks post-MI which was present through 12 wks [Fractional shortening: 0.35±0.01 vs. 0.52±0.01, p<0.01] in Ad-null rats vs. pre-MI. Remote territory (non-infarct area) fibrosis increased by 2 wks post-MI [6±1% vs. 2±1% fibrosis, p<0.01] progressing by 12 wks to 12% fibrosis [p<0.01], consistent with adverse remodeling. Collagen synthesis was upregulated 2.9-fold in CF isolated 12 wks post-MI [p<0.03] and GRK2 activity was increased 1.4-fold [p=0.002]. There was a 42% decrease in intracellular cAMP [p<0.05] and loss of β-agonist-stimulated inhibition of collagen synthesis characteristic of normal CF [3969±1058 vs. 708±95 cmp/mg protein, p<0.01]. Intra-coronary delivery of Ad-GRK2ct following LAD ligation significantly inhibited post-MI LV dysfunction vs. Ad-Null as measured by improved fractional shortening [0.42±0.01 vs. 0.30±0.02, p<0.01] and ejection fraction [72±1% vs. 57±2%, p<0.01]. Ad-GRK2ct also decreased peri-infarct and remote territory fibrosis by 60% [p<0.001]. Consistent with these findings, Ad-GRK2ct resulted in decreased a-SMA, collagen I, and collegen III expression in CF isolated 12 wks post-MI vs. Ad-Null providing evidence of decreased post-MI CF activation and myofibroblast transformation with Ad-GRK2ct. Targeted inhibition of GRK2 and restoration of β-adrenergic signaling/cAMP production in CF may represent a novel therapeutic approach to prevent pathological fibrosis and maladaptive remodeling post-MI.

Sign in / Sign up

Export Citation Format

Share Document