EGFR Inhibition Blocks Palmitic Acid-induced inflammation in cardiomyocytes and Prevents Hyperlipidemia-induced Cardiac Injury in Mice

Li, Weixin; Fang, Qilu; Zhong, Peng; Chen, Lingfeng; Wang, Lintao; Zhang, Yali; Wang, Jun; Li, Xiaokun; Wang, Yi; Wang, Jingying; Liang, Guang

doi:10.1038/srep24580

Cited by 62 publications

(46 citation statements)

References 33 publications

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“…In addition, expression of TLR4-induced genes in lipopolysaccharide-stimulated myeloid cells requires EGFR kinase activity18. We have also found that TLR4 and c-Src mediate palmitic acid-induced EGFR activation in cardiomyocyte-like H9c2 cells34. Thus, we tested whether TLR4/c-Src mediates ox-LDL-induced EGFR activation in macrophages.…”

Section: Resultsmentioning

confidence: 94%

Inhibition of epidermal growth factor receptor attenuates atherosclerosis via decreasing inflammation and oxidative stress

Wang

Huang

et al. 2017

Sci Rep

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Atherosclerosis is a progressive disease leading to loss of vascular homeostasis and entails fibrosis, macrophage foam cell formation, and smooth muscle cell proliferation. Recent studies have reported that epidermal growth factor receptor (EGFR) is involved vascular pathophysiology and in the regulation of oxidative stress in macrophages. Although, oxidative stress and inflammation play a critical role in the development of atherosclerosis, the underlying mechanisms are complex and not completely understood. In the present study, we have elucidated the role of EGFR in high-fat diet-induced atherosclerosis in apolipoprotein E null mice. We show increased EGFR phosphorylation and activity in atherosclerotic lesion development. EGFR inhibition prevented oxidative stress, macrophage infiltration, induction of pro-inflammatory cytokines, and SMC proliferation within the lesions. We further show that EGFR is activated through toll-like receptor 4. Disruption of toll-like receptor 4 or the EGFR pathway led to reduced inflammatory activity and foam cell formation. These studies provide evidence that EGFR plays a key role on the pathogenesis of atherosclerosis, and suggests that EGFR may be a potential therapeutic target in the prevention of atherosclerosis development.

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Section: Resultsmentioning

confidence: 94%

Inhibition of epidermal growth factor receptor attenuates atherosclerosis via decreasing inflammation and oxidative stress

Wang

Huang

et al. 2017

Sci Rep

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“…Li et al (2016) found that EGFR inhibitors reduce myocardial inflammation, fibrosis, apoptosis and dysfunction in two murine obesity models, together with inhibiting palmitate-dependent inflammation and apoptosis in H9c2 cells. This is consistent with saturated fatty acid inhibition of NRG1b activation of myocyte PI3K/Akt signalling, an effect countered by a monounsaturated fatty acid (oleate) (Miller et al, 2009).…”

Section: Obesity/dyslipidemiamentioning

confidence: 95%

“…Over-activity of EGFR in diabetes/metabolic disorders, for example, may exaggerate inflammation and oxidative stress in cardiac Li et al, 2016) and other tissues (Fang et al, 2016). Inhibitors of EGFR have also been shown to reduce insulin-resistance (Prada et al, 2009), atherosclerosis and vascular dysfunction in (Choi et al, 2012) in models of obesity, dyslipidemia and diabetes.…”

Section: Understanding Complexities In Egfr Modulationmentioning

confidence: 99%

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

Reichelt

O’Brien

Thomas

et al. 2017

The International Journal of Biochemistry & Cell Biology

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“…The molecular components of the TLR4 receptor complex formed in response to FnIII domains are not well understood. Based on recent findings linking TLR4 to epidermal growth factor receptor (EGFR)/ Src signaling, [26][27][28] we evaluated whether either EGFR or Src kinases contributed to IL-8 release initiated by FnEDA and FnIII-1c. As shown in Fig.…”

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confidence: 99%

TLR4 Ligands Selectively Synergize to Induce Expression of IL-8

Valenty

Longo

Horzempa

et al. 2017

Advances in Wound Care

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Objective: Dysfunctional remodeling of the extracellular matrix contributes to the formation of TLR-dependent feed forward loops that drive chronic inflammation. We have previously shown that two Type III domains of Fibronectin, FnEDA and FnIII-1c, cooperate to induce the synergistic release of interleukin 8 (IL-8) from dermal fibroblasts. We now identify steps in the TLR4 pathway where synergy can be demonstrated as well as additional kinases functioning in fibronectin activation of TLR4 signaling. We also evaluate the ligand and cell-type specificity of this synergistic response. Approach: FnEDA, FnIII-1c, and lipopolysaccharide (LPS)-induced genes in fibroblasts were analyzed by a quantitative reverse transcription-polymerase chain reaction (qPCR) and protein was measured by an enzyme-linked immunosorbent assay (ELISA). Kinases functioning in gene expression were identified by using specific inhibitors. Activated TLR4-dependent effector molecules were identified by cell fractionation and Western blot and quantified by image analysis. Results: The addition of FnEDA and FnIII-1c to dermal fibroblasts resulted in a synergistic increase in the expression of IL-8, tumor necrosis factor alpha (TNF-a), and vascular cell adhesion molecule (VCAM-1). Synergy between these domains was detected at the level of nuclear factor kappa-light chain enhancer of activated B cells (NF-jB) and inhibitor of kappa B kinase (IKK) activation. Induction of IL-8 by fibronectin ligands was partially attenuated in the presence of inhibitors to either epidermal growth factor receptor or Src kinases. FnIII-1c also synergized with LPS to induce IL-8 in dermal fibroblasts, whereas the combined effect of FnEDA and LPS on IL-8 synthesis was additive. In contrast, synergistic responses to these ligands were not observed in THP-1 monocytic cells. Innovation: The data suggest that chronic inflammation may be driven by matrix-and pathogen-derived TLR4 ligands that work in synergy to promote an exuberant innate response. Conclusion: The data suggest that the molecular mechanism underlying synergistic responses to TLR4 ligands lies upstream of IKK activation, likely in the molecular composition of the TLR4 receptor complex that assembles in response to each ligand. In addition, synergistic responses to TLR4 activation may be both cell-type and ligand specific. Keywords: fibronectin, TLR4, IL-8, inflammation, LPS INTRODUCTIONProlonged inflammation in response to injury is a contributory factor to the development of chronic wounds. Extracellular matrix (ECM)- fibronectin has also been shown to promote fibro-inflammatory responses in several mouse models. 9,17,18 The EDA domain of fibronectin can activate TLR4 signaling as either the individual domain, proteolytic fragment or in the context of the intact molecule. 19,20 Being responsible for matrix synthesis, assembly, and turnover, stromal fibroblasts are in constant dialogue with the fibronectin matrix in its polymerized and fragmented forms. Changes in tissue mechanical forces have been shown to caus...

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EGFR Inhibition Blocks Palmitic Acid-induced inflammation in cardiomyocytes and Prevents Hyperlipidemia-induced Cardiac Injury in Mice

Cited by 62 publications

References 33 publications

Inhibition of epidermal growth factor receptor attenuates atherosclerosis via decreasing inflammation and oxidative stress

Inhibition of epidermal growth factor receptor attenuates atherosclerosis via decreasing inflammation and oxidative stress

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

TLR4 Ligands Selectively Synergize to Induce Expression of IL-8

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