scholarly journals Hyperglycemia enhances function and differentiation of adult rat cardiac fibroblasts

2014 ◽  
Vol 92 (7) ◽  
pp. 598-604 ◽  
Author(s):  
Patricia E. Shamhart ◽  
Daniel J. Luther ◽  
Ravi K. Adapala ◽  
Jennifer E. Bryant ◽  
Kyle A. Petersen ◽  
...  
Keyword(s):  
High Glucose ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Cardiac Fibroblast ◽  
Collagen I ◽  
Akt Phosphorylation ◽  
Adult Rat ◽  
Proliferation And Differentiation ◽  
Low Glucose ◽  
Glucose Treatment

Diabetes is an independent risk factor for cardiovascular disease that can eventually cause cardiomyopathy and heart failure. Cardiac fibroblasts (CF) are the critical mediators of physiological and pathological cardiac remodeling; however, the effects of hyperglycemia on cardiac fibroblast function and differentiation is not well known. Here, we performed a comprehensive investigation on the effects of hyperglycemia on cardiac fibroblasts and show that hyperglycemia enhances cardiac fibroblast function and differentiation. We found that high glucose treatment increased collagen I, III, and VI gene expression in rat adult cardiac fibroblasts. Interestingly, hyperglycemia increased CF migration and proliferation that is augmented by collagen I and III. Surprisingly, we found that short term hyperglycemia transiently inhibited ERK1/2 activation but increased AKT phosphorylation. Finally, high glucose treatment increased spontaneous differentiation of cardiac fibroblasts to myofibroblasts with increasing passage compared with low glucose. Taken together, these findings suggest that hyperglycemia induces cardiac fibrosis by modulating collagen expression, migration, proliferation, and differentiation of cardiac fibroblasts.

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.

Relaxin Inhibits Cardiac Fibrosis in Diabetic Rats: Roles of Protein Kinase Cδ

2017 ◽  
Vol 126 (05) ◽  
pp. 298-305 ◽  
Author(s):  
Ping Wang ◽  
Meng Li ◽  
Lei Dong ◽  
Hui Chen ◽  
Wei Su ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Western Blot ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Diabetic Rats ◽  
Collagen I ◽  
Control Group ◽  
Proliferation And Differentiation ◽  
Protein Kinase Cδ

AbstractRelaxin (Rlx) is known to antagonize diabetic cardiac fibrosis. However, its mechanism is poorly understood. Protein kinase Cδ (PKCδ) plays a crucial role in diabetic cardiomyopathy (DCM). This study explored the involvement of PKCδ in Rlx’s capacity of suppressing cardiac fibrosis in a rat model of type 2 diabetes mellitus (DM). Type 2 DM of 8-week-old male Sprague–Dawley (SD) rats was induced by a high-fat diet and the injection of streptozocin (STZ, 40 mg/kg). Fourteen-week-old rats with DM and rats in control group which were pre-treated for 1 week with human recombinant relaxin (rhRlx, 30 μg/kg.d), were assessed to detect cardiac fibrosis and PKCδ expression with Western blot. Cardiac fibroblasts of neonatal rats were treated for 72 h with rhRlx (100 ng/ml) under high glucose (HG). Western blot was utilized for detecting the membranous and cytoplasmic protein expressions of PKCδ. The effects of rhRlx and PKCδ inhibitor (rottlerin) were assessed either alone or in combination on the HG-induced proliferation and differentiation of cardiac fibroblasts and the release of collagen I.Rlx treatment inhibited the differentiation of cardiac fibroblasts and the expression of collagen I. The expression of PKCδ was regulated by Rlx in diabetic rats and cardiac fibroblasts under HG condition. The effects of Rlx upon the proliferation and differentiation of cardiac fibroblasts and the excretion of collagen I under HG were blunted by rottlerin. Rlx suppressed cardiac fibrosis in type 2 diabetic rats. This beneficial effect was associated with its ability of modulating the expression of PKCδ.

scholarly journals Calcium Signal Pathway is Involved in Prostaglandin E2 Induced Cardiac Fibrosis in Cardiac Fibroblasts

2018 ◽  
Vol 21 ◽  
pp. 326-339
Author(s):  
Yunzi Ma ◽  
Zhongbao Yue ◽  
Boyu Zhang ◽  
Min Yang ◽  
Haiyan Lao ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Prostaglandin E2 ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Smooth Muscle Actin ◽  
Signal Pathway ◽  
Tissue Growth ◽  
Collagen I ◽  
Calcium Signal ◽  
Adult Rat

Prostaglandin E2 (PGE2), one of the arachidonic acid metabolites synthetized from arachidonic acid through cyclooxygenase (COX) catalysis, demonstrates multiple physiological and pathological actions through different subtypes of EP receptors. PURPOSE: The present study was designed to explore the effects of PGE2 on cardiac fibrosis and the involved mechanism. METHODS: We used western blot analysis, real-time quantitative PCR and immunostaining etc. to testify the mechanism. RESULTS: Our data showed that in cultured adult rat cardiac fibroblasts (CFs), PGE2 effectively promoted the expression of α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF)，fibronectin (FN), Collagen I and induced [Ca2+]i increase. Besides, calcium increase evoked by PGE2 is mediated by virtue of EP1 activation. Instead of EP3 or EP4, inhibition of EP1 attenuated PGE2-stimulated upregulation of α-SMA，CTGF, FN, collagen I and [Ca2+]i, as well as the nuclear factor of activated T cell cytoplasmic 4 protein (NFATc4) translocation. CONCLUSIONS: PGE2 may promote cardiac fibrosis via EP1 receptor and calcium signal pathway.

scholarly journals Resveratrol inhibits high glucose-induced activation and cytokine production of isolated primary pancreatic stellate cells

2019 ◽  
Vol 8 (3) ◽  
pp. 35-47
Author(s):  
Zhen Zhou ◽  
Xiaodong Sun ◽  
Rao Yan ◽  
Jinfeng An ◽  
Xinjian Zhou ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
High Glucose ◽  
Stellate Cells ◽  
Collagen I ◽  
Pancreatic Stellate Cells ◽  
Mrna Levels ◽  
Tnf Α ◽  
Low Glucose ◽  
Glucose Treatment ◽  
Pharmacologically Active

Objective: Activation of pancreatic stellate cells (PSCs) is detrimental to pancreas function by promoting pancreatic fibrosis. Resveratrol is a natural and pharmacologically active compound. This study is to investigate the effect of resveratrol on the bilogical behavior of PSCs under high glucose condition.Methods: Isolated primary mouse PSCs were cultured in low glucose ( 5.5 mmol/L glucose, LG group ) medium, high glucose ( 25 mmol/L glucose, HG group ) medium and treated with  resveratrol ( 25 μmol/L or 50 μmol/L). Cell proliferation was examined using MTT assay. The expression of α-SMA and collagen I were determined using Western blotting. Alpha-SMA expression was also determined using immunocytochemistry staining. IL-1, IL-6, and TNF-α mRNA levels and secretion levels in media of PSCs were determined using qRT-PCR and ELISA respectively.Results: Cell Proliferation,  α-SMA and collagen I  expression levels, IL-1, IL-6, and TNF-α mRNA levels and secretion levels of PSCs were increased after high glucose treatment, compared with low glucose treatment. They were significantly decreased in PSCs treated with both high glucose and resveratrol, compared with high glucose treatment.Conclusion: Resveratrol inhibited high glucose induced PSCs proliferation, activation，cytokine expression and secretion in PSCs. Therefore, resveratrol can be potentially used in therapy of diseases such as type 2 diabetes mellitus (T2DM), pancreatitis and pancreatic cancer where PSCs is activated by high glucose.

DYNAMIC BIOREACTOR MODEL TO MIMIC EARLY CARDIAC FIBROSIS IN DIABETES

2021 ◽  
pp. 2150047
Author(s):  
SPENCER MARSH ◽  
MADELINE RAUDAT ◽  
BETHANY LEFEBER ◽  
LAURA BETH HERNDON ◽  
HOWARD HERBERT ◽  
...  
Keyword(s):  
High Glucose ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Tissue Injury ◽  
Cardiac Fibroblasts ◽  
Cardiac Fibroblast ◽  
Mechanical Stimuli ◽  
Adequate Model ◽  
Fibroblast Activation ◽  
Glucose Levels

In clinical diabetic cardiomyopathy, hyperglycemia and dyslipidemia induce tissue injury, activation of cardiac fibroblasts and interstitial and perivascular fibrosis. Myofibroblasts repair the injured tissue by increasing collagen deposition in the cardiac interstitium and suppressing the activity of matrix metalloproteinases. The goal of this study was to find an ideal model to mimic the effect of high glucose concentration on human cardiac fibroblast activation. The profibrotic role of the transforming growth factor-[Formula: see text] (TGF-[Formula: see text]) and the protective modulation of nitric oxide were examined in two-dimensional and three-dimensional cell culture models, as well as tissue engineering models, that involved the use of cardiac fibroblasts cultured within myocardial matrix scaffolds mounted in a bioreactor that delivered biochemical and mechanical stimuli. Results showed that high glucose levels were potent pro-fibrotic stimuli. In addition, high glucose levels in concert with TGF-[Formula: see text] constituted very strong signals that induced human cardiac fibroblast activation. Cardiac fibroblasts cultured within decellularized myocardial scaffolds and exposed to biochemical and mechanical stimuli represented an adequate model for this pathology. In conclusion, the bioreactor platform was instrumental in establishing an in vitro model of early fibrosis; this platform could be used to test the effects of various agents targeted to mitigate the fibrotic processes.

Abstract 237: Sex-specific Regulation Of Collagen I And III Expression By 17β-estradiol In Rat Cardiac Fibroblasts: Role Of Estrogen Receptors

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Elke Dworatzek ◽  
Shokoufeh Mahmoodzadeh ◽  
Sandra Kunze ◽  
Vera Regitz-Zagrosek
Keyword(s):  
Sex Differences ◽  
Western Blot ◽  
Estrogen Receptors ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Collagen I ◽  
Female Rats ◽  
17Β Estradiol ◽  
Specific Regulation

Clinical and animal studies showed in female pressure-overloaded hearts less cardiac fibrosis and collagen I and III gene expression compared to males, suggesting an inhibitory effect of 17β-Estradiol (E2) on collagens. Therefore we investigated the role of E2 and estrogen receptors (ER) on collagen I and III expression in isolated rat cardiac fibroblasts from both sexes. Cardiac fibroblasts were isolated from adult male and female Wistar rats, and treated with E2 (10-8M), vehicle, ERα and ERβ-agonist (10-7M) and/or pre-treated with ICI 182,780 (10-5M) for 24h. Cellular localization of ER in cardiac fibroblasts with/without E2 was detected by immunofluorescence staining, and expression of both ER was determined by western blot. Expression of collagen I and III was determined by qRT-PCR and western blot. E2-treatment led to a nuclear translocation of ERα and ERβ in cardiac fibroblasts, suggesting the functional activity of ER as transcription factors. Furthermore in cardiac fibroblasts from female rats E2 led to a significant down-regulation of collagen I and III gene and protein expression. In contrast there was a significant increase of collagen I and III levels in fibroblasts isolated from male rat hearts by E2. E2-effect could be inhibited by ICI 182, 780 indicating the involvement of ER. In cardiac fibroblasts from female rats, ERα-agonist treatment led to a significant down-regulation of collagen I and III mRNA level, but ERβ-agonist had no effects. In contrast, ERβ-agonist treatment of cardiac fibroblasts from males increased collagen I and III mRNA, but no changes with ERα agonist-treatment were detected. ERα protein levels displayed no sex differences at basal level. After E2-treatment ERα protein was up-regulated in male cells, but decreased in cardiac fibroblasts from females. ERβ protein was higher in female cells compared to males, but the expression was not regulated by E2 in both sexes. Sex-specific regulation of collagen I and III expression by E2 in cardiac fibroblasts might be responsible for sex-differences in cardiac fibrosis. This might be due to sexually dimorphic ER expression and regulation. Understanding how E2 and ER mediate sex-differences in cardiac remodeling may help to design sex-specific pharmacological interventions.

Abstract 89: 17beta-Estradiol-activated Estrogen Receptors Attenuate Cardiac Fibrosis Through Inhibition of Collagen I and III Expression in Female Hearts

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Elke Dworatzek ◽  
Shokoufeh Mahmoodzadeh ◽  
Christina Westphal ◽  
Daniela Fliegner ◽  
Vera Regitz-Zagrosek
Keyword(s):  
Estrogen Receptors ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Collagen I ◽  
Sham Operation ◽  
Female Rat ◽  
Female Mice ◽  
Gene And Protein Expression

Objectives: Female pressure-overloaded hearts show less fibrosis compared with males. 17β-Estradiol (E2) attenuates cardiac fibrosis in female mice. Whether this is mediated by direct E2-effects on collagen synthesis is still unknown. Therefore, we investigated the role of E2 and estrogen receptors (ER) on collagen I and III expression and analyzed involved mechanisms. Methods: Female C57BL/6J mice (7 weeks) underwent sham operation, ovariectomy (OVX), OVX with E2-supplementation (390mg E2-containing pellets) or placebo. After 2 weeks, animals underwent transverse aortic constriction (TAC) or sham surgery. Mice were sacrificed after 9 weeks. Collagen amount, collagen I and III protein in left ventricular tissue were detected by Sirius Red and antibody staining, respectively. Gene and protein expression were determined by quantitative Real-Time PCR and Western blot. Adult female rat cardiac fibroblasts were treated with E2 (10 -8 M), vehicle, ERα- and β-agonists (10 -7 M) for 24h or pre-treated with PD98059 for 1h. ER binding to the collagen I and III promoter was analyzed by chromatin immunoprecipitation assays. Findings: In female OVX mice, undergoing TAC surgery, E2-supplementation significantly reduced collagen deposition, collagen I and III mRNA and protein levels in comparison with mice without E2. In female rat cardiac fibroblasts, E2 significantly down-regulated collagen I and III mRNA and protein level. Specific ER-agonist-treatment showed that E2-mediated regulation of collagen I and III expression was mediated via activation of ERα, but not ERβ. Further, upon E2-treatment, ERα was phosphorylated at Ser118, which occurred by E2-induced activation of ERK1/2 signaling. Furthermore, we could show that ERα and ERβ bind to two putative half-palindromic estrogen response elements within the collagen I and III promoter in female cardiac fibroblasts. Conclusion: E2 inhibits cardiac collagen I and III mRNA and protein in female mice under pressure overload. Data from rat female cardiac fibroblasts suggest that this is mediated via E2-activated ERK1/2 signaling and ERα, which binds with ERβ to the collagen I and III promoter. Understanding of how E2/ER attenuate collagen I and III expression in pathological hypertrophy may improve therapy.

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 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.

Cardiac Fibroblast Diversity

2020 ◽  
Vol 82 (1) ◽  
pp. 63-78 ◽  
Author(s):  
Michelle D. Tallquist
Keyword(s):  
Extracellular Matrix ◽  
Single Cell ◽  
Future Development ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Pathological Condition ◽  
Cardiac Fibroblast ◽  
Lineage Tracing ◽  
Single Cell Sequencing ◽  
Disease States

Cardiac fibrosis is a pathological condition that occurs after injury and during aging. Currently, there are limited means to effectively reduce or reverse fibrosis. Key to identifying methods for curbing excess deposition of extracellular matrix is a better understanding of the cardiac fibroblast, the cell responsible for collagen production. In recent years, the diversity and functions of these enigmatic cells have been gradually revealed. In this review, I outline current approaches for identifying and classifying cardiac fibroblasts. An emphasis is placed on new insights into the heterogeneity of these cells as determined by lineage tracing and single-cell sequencing in development, adult, and disease states. These recent advances in our understanding of the fibroblast provide a platform for future development of novel therapeutics to combat cardiac fibrosis.

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