Role for high-glucose-induced protein <i>O</i>-GlcNAcylation in stimulating cardiac fibroblast collagen synthesis

Aguilar, Hugo; Fricovsky, Eduardo; Ihm, Sang Hyun; Schimke, Magdalena; Maya-Ramos, Lisandro; Aroonsakool, Nakon; Ceballos, Guillermo; Dillmann, Wolfgang H.; Villarreal, Francisco; Ramírez-Sánchez, Israel

doi:10.1152/ajpcell.00251.2013

Cited by 66 publications

(55 citation statements)

References 43 publications

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“…Therefore, overexpression of IL-6 is a likely mechanism by which FBs induce TGF-β1-activation, leading to increased myocardial apoptosis caused by hypoxic stimulation. Our findings were supported by the study of Aguilar et al, 24 where culturing of cardiac FBs in high-glucose media led to significant increases in TGF-β1 and Smad2/3, leading to increases in collagen levels. Thus, hypoxic IL-6 overexpressing Figure 6 Continued.…”

Section: Discussionsupporting

confidence: 90%

Hypoxia-stimulated cardiac fibroblast production of IL-6 promotes myocardial fibrosis via the TGF-β1 signaling pathway

Wang

Zhao

Pan

et al. 2016

Laboratory Investigation

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Interlukin-6 (IL-6) is a multifunctional cytokine produced by several cell types that has a role in fibrosis. Fibroblasts (FBs) maintain this underlying pathogenic change through regulation of IL-6 production; however, its potential functional role in regulating surrounding cellular structural changes during ischemic myocardial remodeling remains unexplored. Here, we generated FBs, cardiomyocytes (CMs), and blood vascular endothelial cells (ECs) from the ventricles of neonatal rats. IL-6 was then overexpressed in FBs and the cells were treated with IL-6 receptor inhibitor (IL6RI), TGF-β1 receptor inhibitor (TβRI), or MMP2/MMP9 inhibitor (MMPI) using monoculture or coculture models under hypoxic conditions. The results indicate that overexpression of IL-6 is sufficient to induce myofibroblastic proliferation, differentiation, and fibrosis, probably via increased TGF-β1-mediated MMP2/MMP3 signaling. The use of IL6RI, TβRI, or MMPI diminished these effects. In addition, IL-6 activated the apoptosis-associated factors Caspase3 and Smad3, and decreased the expression of anti-apoptotic factor Bcl2, resulting in apoptosis of CMs under hypoxic coculture: IL6RI or TβRI inhibited these effects. Unexpectedly, IL-6-overexpressing FBs significantly increased the angiogenesis of ECs, which involved significant increases in the expression of proangiogenic growth factors. Treatment of FBs with IL6RI or TβRI in coculture with ECs reduced the levels of secreted proangiogenic growth factors, and the angiogenesis of ECs was significantly downregulated. Thus, IL-6 functions in ischemic myocardial remodeling through multifunctional reprogramming of hypoxia-associated FBs towards fibrosis via upregulation of the TGF-β1 signaling pathway.

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Section: Discussionsupporting

confidence: 90%

Hypoxia-stimulated cardiac fibroblast production of IL-6 promotes myocardial fibrosis via the TGF-β1 signaling pathway

Wang

Zhao

Pan

et al. 2016

Laboratory Investigation

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“…Hyperglycemia (high glucose) is a manifestation presented in DM [7]. It has been reported high glucose stimulates fibroblast proliferation [14], activates the transcription and secretion of extracellular matrix proteins [15], and transduces fibrogenic signals through ROS generation [16]. In addition, pro-inflammatory cytokines and chemokines may recruit fibrogenic leukocyte subsets in the cardiac interstitium.…”

Section: Discussionmentioning

confidence: 99%

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

Tsai

Loh

Lee

et al. 2018

Cell Physiol Biochem

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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.

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“…The regulation of these pathways has been shown to be responsive to signals that also induce autophagy, such as nutritional deprivation [104–107], cell cycle and development [108, 109], and cellular stress [59, 110–112]. As proposed earlier, O-GlcNAc signaling could regulate autophagy via modification of CopII coat proteins.…”

Section: Intracellular Glycosylation: a Transduction Mechanism In Autmentioning

confidence: 98%

Molecular Functions of Glycoconjugates in Autophagy

Fahie

Zachara

2016

Journal of Molecular Biology

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Glycoconjugates, glycans, carbohydrates, and sugars: these terms encompass a class of biomolecules that are diverse in both form and function ranging from free oligosaccharides, glycoproteins and proteoglycans, to glycolipids that make up a complex glycan-code that impacts normal physiology and disease. Recent data suggests that one mechanism by which glycoconjugates impact physiology is through the regulation of the process of autophagy. Autophagy is a degradative pathway necessary for differentiation, organism development, and the maintenance of cell and tissue homeostasis. In this review, we will highlight what is known about the regulation of autophagy by glycoconjugates focusing on signaling mechanisms from the extracellular surface and the regulatory roles of intracellular glycans. Glycan signaling from the extracellular matrix converges on “master” regulators of autophagy including AMPK and mTORC1, thus impacting their localization, activity and/or expression. Within the intracellular milieu, gangliosides are constituents of the autophagosome membrane, a subset of proteins composing the autophagic machinery are regulated by glycosylation, and oligosaccharide exposure in the cytosol triggers an autophagic response. The examples discussed provide some mechanistic insights into glycan regulation of autophagy and reveals areas for future investigation.

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

Cited by 66 publications

References 43 publications

Hypoxia-stimulated cardiac fibroblast production of IL-6 promotes myocardial fibrosis via the TGF-β1 signaling pathway

Hypoxia-stimulated cardiac fibroblast production of IL-6 promotes myocardial fibrosis via the TGF-β1 signaling pathway

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

Molecular Functions of Glycoconjugates in Autophagy

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