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 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.

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 445: A Pro-Fibrotic Role of Interleukin-4 in Cardiac Remodeling and Dysfunction

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Hongmei Peng ◽  
Oscar Carretero ◽  
Xiao-Ping Yang ◽  
Pablo Nakagawa ◽  
Jiang Xu ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Interleukin 4 ◽  
Ang Ii ◽  
Collagen Production ◽  
And Function ◽  
First Time ◽  
Mini Pump

Elevated interleukin-4 (IL-4) levels are positively related to cardiac fibrosis in heart failure and hypertension. Using Balb/c exhibiting high circulating IL-4, Balb/c- Il4 tm2Nnt (IL-4 knockout with Balb/c background, IL-4 -/- ) and C57BL/6 mice, as well as cultured cardiac fibroblasts (CFs), we hypothesized that 1) high levels of IL-4 result in cardiac fibrosis, making the heart susceptible to angiotensin II (Ang II)-induced damage, and 2) IL-4 potently stimulates collagen production by CFs. Each strain (9- to 12-week old male) received vehicle or Ang II (1.4 mg/kg/day, s.c. via osmotic mini-pump) for 8 weeks. Cardiac fibrosis and function were determined by histology and echocardiography, respectively. Compared to C57BL/6, Balb/c mice had doubled interstitial collagen in the heart, enlarged left ventricle and decreased cardiac function along with elevated cardiac IL-4 protein (1.00±0.08 in C57BL/6 vs 2.61±0.46 in Balb/c, p <0.05); all those changes were significantly attenuated in IL-4 -/- (Table 1). Ang II further deteriorated cardiac fibrosis and dysfunction in Balb/c; these detrimental effects were attenuated in IL-4 -/- , although the three strains had a similar level of hypertension. In vitro study revealed that IL-4Rα was constitutively expressed in CFs (Western blot), and IL-4 potently stimulated collagen production by CFs (hydroxproline assay, from 18.89±0.85 to 38.81±3.61 μg/mg at 10 ng/ml, p <0.01). Our study demonstrates for the first time that IL-4, as a potent pro-fibrotic cytokine in the heart, contributes to cardiac fibrotic remodeling and dysfunction. Thus IL-4 may be a potential therapeutic target for cardiac fibrosis and dysfunction.

scholarly journals miR-21 is upregulated, promoting fibrosis and blocking G2/M in irradiated rat cardiac fibroblasts

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10502
Author(s):  
Huan Guo ◽  
Xinke Zhao ◽  
Haixiang Su ◽  
Chengxu Ma ◽  
Kai Liu ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Target Genes ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Differentially Expressed Gene ◽  
Stem Loop ◽  
Cardiac Morbidity ◽  
Increased Risk ◽  
And Function

Background Radiation exposure of the thorax is associated with a greatly increased risk of cardiac morbidity and mortality even after several decades of advancement in the field. Although many studies have demonstrated the damaging influence of ionizing radiation on cardiac fibroblast (CF) structure and function, myocardial fibrosis, the molecular mechanism behind this damage is not well understood. miR-21, a small microRNA, promotes the activation of CFs, leading to cardiac fibrosis. miR-21 is overexpressed after irradiation; however, the relationship between increased miR-21 and myocardial fibrosis after irradiation is unclear. This study was conducted to investigate gene expression after radiation-induced CF damage and the role of miR-21 in this process in rats. Methods We sequenced irradiated rat CFs and performed weighted correlation network analysis (WGCNA) combined with differentially expressed gene (DEG) analysis to observe the effect on the expression profile of CF genes after radiation. Results DEG analysis showed that the degree of gene changes increased with the radiation dose. WGCNA revealed three module eigengenes (MEs) associated with 8.5-Gy-radiation—the Yellow, Brown, Blue modules. The three module eigengenes were related to apoptosis, G2/M phase, and cell death and S phase, respectively. By blocking with the cardiac fibrosis miRNA miR-21, we found that miR-21 was associated with G2/M blockade in the cell cycle and was mainly involved in regulating extracellular matrix-related genes, including Grem1, Clu, Gdf15, Ccl7, and Cxcl1. Stem-loop quantitative real-time PCR was performed to verify the expression of these genes. Five genes showed higher expression after 8.5 Gy-radiation in CFs. The target genes of miR-21 predicted online were Gdf15 and Rsad2, which showed much higher expression after treatment with antagomir-miR-21 in 8.5-Gy-irradiated CFs. Thus, miR-21 may play the role of fibrosis and G2/M blockade in regulating Grem1, Clu, Gdf15, Ccl7, Cxcl1, and Rsad2 post-irradiation.

Abstract P153: Role of Nonreceptor Tyrosine Kinases in Cardiac Fibrosis in a Mouse Model of Pressure Overload Hypertrophy

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Sundaravadivel Balasubramanian ◽  
Harinath Kasiganesan ◽  
Lakeya Quinones ◽  
Yuhua Zhang ◽  
Amy Bradshaw ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Heart Diseases ◽  
Pressure Overload ◽  
In Vivo Studies ◽  
Survival Pathways ◽  
And Function ◽  
Nonreceptor Tyrosine Kinases

During prolonged hypertrophic insult to the myocardium, while the function of cardiomyocytes needs to be protected, the hyperactivation of cardiac fibroblasts has to be curbed to prevent fibrosis. Previously, we showed that integrin-mediated non-receptor tyrosine kinase (NRTK) activation is required for normal functioning of both cardiac fibroblasts and cardiomyocytes. We hypothesized that inhibition of NRTKs in cardiac fibroblasts without affecting cardiomyocytes would be beneficial to the stressed myocardium. Our initial studies using kinase inactive forms of Src, Pyk2 and FAK expressed adenovirally in isolated primary cardiac fibroblasts showed that the pro-fibrotic signaling events as studied by fibronectin and collagen deposition are downregulated. Our in vivo studies in mouse transverse aortic constriction (TAC) model suggest that dasatinib, a multikinase NRTK inhibitor administration via a peritoneally implanted mini-osmotic pump is able to preserve ventricular geometry and function and reduce the accumulation of fibrotic extracellular matrix (ECM) proteins upon 4 wk pressure overload. Data obtained from cell culture experiments with kinase inactive NRTKs and dasatinib suggest that NRTK inhibition is able to reduce the proliferation, migration and mitogenic signaling in cardiac fibroblasts without affecting the cell survival pathways in cardiomyocytes. These data indicate that NRTKs play a significant pro-fibrotic role in cardiac fibroblasts and curbing the activity of NRTKs could be a potential therapeutic approach to treat fibrosis in hypertrophic heart diseases.

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.

scholarly journals Effect of ALDH2 on High Glucose-Induced Cardiac Fibroblast Oxidative Stress, Apoptosis, and Fibrosis

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Xiaoyu Gu ◽  
Tingting Fang ◽  
Pinfang Kang ◽  
Junfeng Hu ◽  
Ying Yu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Expression ◽  
High Glucose ◽  
Collagen Type ◽  
Cardiac Fibroblasts ◽  
Collagen Type I ◽  
Cardiac Fibroblast ◽  
Type I ◽  
Mrna Levels ◽  
Neonate Rat

Our study aimed firstly to observe whether ALDH2 was expressed in neonate rat cardiac fibroblasts, then to investigate the effect of activation of ALDH2 on oxidative stress, apoptosis, and fibrosis when cardiac fibroblasts were subjected to high glucose intervention. Cultured cardiac fibroblasts were randomly divided into normal (NG), NG + Alda-1, high glucose (HG), HG + Alda-1, HG + Alda-1 + daidzin, HG + daidzin, and hypertonic groups. Double-label immunofluorescence staining, RT-PCR, and Western blot revealed ALDH2 was expressed in cardiac fibroblasts. Compared with NG, ALDH2 activity and protein expression were reduced, and cardiac fibroblast proliferation, ROS releasing, 4-HNE protein expression, collagen type I and III at mRNA levels, and the apoptosis rate were increased in HG group. While in HG + Alda-1 group, with the increases of ALDH2 activity and protein expression, the cardiac fibroblast proliferation and ROS releasing were decreased, and 4-HNE protein expression, collagen type I and III at mRNA levels, and apoptosis rate were reduced compared with HG group. When treated with daidzin in HG + Alda-1 group, the protective effects were inhibited. Our findings suggested that ALDH2 is expressed in neonate rat cardiac fibroblasts; activation of ALDH2 decreases the HG-induced apoptosis and fibrosis through inhibition of oxidative stress.

Alterations in Cardiac Structure and Function in a Murine Model of Chronic Alcohol Consumption

2012 ◽  
Vol 18 (3) ◽  
pp. 453-461 ◽  
Author(s):  
Brittany A. Law ◽  
Scott P. Levick ◽  
Wayne E. Carver
Keyword(s):  
Transforming Growth Factor Beta ◽  
Time Course ◽  
Structural Changes ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Cardiomyocyte Hypertrophy ◽  
Histological Techniques ◽  
Number Of Factors ◽  
Mrna Analysis ◽  
And Function

AbstractMale, wild-type, FVB strain mice were fed a nutritionally complete liquid diet supplemented with 4% ethanol v/v over a time course of 1, 2, 4, 8, 12, and 14 weeks. Controls were offered an isocaloric liquid equivalent and pair fed with their ethanol counterparts. Changes in cardiac physiology were assessed at respective time points via echocardiography. Additionally, the use of histological techniques, mRNA analysis, apoptosis determination, and immunohistochemistry were employed to determine the functional and structural changes on the heart. Echocardiograph analysis revealed a compensatory phase that occurred early in the time course (1–8 weeks) and decompensation reverting toward heart failure at weeks 12 and 14. Throughout the study, an increase in cardiomyocyte hypertrophy, cardiac fibrosis, apoptosis, TGF-β, and the presence of α-SMA-positive cells were determined. A compensatory period in mice treated with ethanol occurred early followed by a transition to a dilated phenotype over time. A number of factors may be involved in this process including the activation of myofibroblasts and their fibrotic activities that is correlated with the presence of transforming growth factor beta.

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