Oxidized Low-Density Lipoprotein Promotes Macrophage Lipid Accumulation via the Toll-Like Receptor 4-Src Pathway

Yang, Ke; Wang, Xiaoqun; Liu, Zhuhui; Lü, Lin; Mao, Jinyan; Meng, Hua; Wang, Yanan; Hu, Yong; Zeng, Ying; Zhang, Xiaojie; Chen, Qiujing; Liu, Yan; Shi, Weifeng

doi:10.1253/circj.cj-15-0345

Cited by 22 publications

(14 citation statements)

References 40 publications

(8 reference statements)

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“…Recent studies have suggested that EGFR can also be activated without the typical ligands29, and it can function in intracellular membranes30. Toll-like receptor 4 (TLR4) has been reported to be directly activated by ox-LDL and mediate pathological pathways and phenotypes313233. In addition, expression of TLR4-induced genes in lipopolysaccharide-stimulated myeloid cells requires EGFR kinase activity18.…”

Section: Resultsmentioning

confidence: 99%

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: 99%

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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“…During the development of AS, persistently existing chronic inflammation finally resulted in the formation of damage within vascular endothelium, along with lipid deposition and the infiltration of inflammatory cells. Macrophages is vitally involved by swallowing over loaded lipid which in turn leaded to the disorders of metabolism and decreased anti-apoptosis ability of cells [26]. …”

Section: Discussionmentioning

confidence: 99%

“…TLR4 is a most intensively studied member of TLRs family, which is extensively expressed on macrophages. Previous studies have demonstrated that TLR4 was involved in the regulation of macrophage lipid accumulation [21-25], and it is essential for ox-LDL-induced lipid uptake in macrophages [2, 26]. …”

Section: Introductionmentioning

confidence: 99%

PTPRO Promotes Oxidized Low-Density Lipoprotein Induced Oxidative Stress and Cell Apoptosis through Toll-Like Receptor 4/Nuclear Factor κB Pathway

Liang

Wang

et al. 2017

Cell Physiol Biochem

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Background/Aims: Critical roles of phosphatase receptor type O (PTPRO) and toll-like receptor 4 (TLR4) have been implicated in inflammation. However, little is known about their functional effects on atherosclerosis (AS). We aim to study their potential function in AS. Methods: An oxidized low-density lipoprotein (ox-LDL) induced AS model constructed with PTPRO over-expressing RAW264.7 cells and PTPRO knockout macrophages. Cell apoptosis was assayed by flow cytometry and fatty accumulation was evaluated by oil red staining. The production of ROS (reactive oxygen species), SOD (superoxide dismutase), MDA (malondialdehyde), TC (Triglyceride), and TG (total cholesterol) was evaluated. Western blot was performed to detect the expression of CD36, TLR4 and nuclear factor kB (NF-κB). Results: PTPRO expression was promoted in a dose-dependent and time-dependent manner following ox-LDL challenging. In PTPRO-over-expressing cells, CD36 expression and the level of oil-red staining, TC and TG were increased; ROS production, MDA and level of cell apoptosis were improved, but SOD was reduced. However, in PTPRO knockout cells opposite results were found. TLR4 and NF-κB/p65 phosphorylation was significantly enhanced in PTPRO over-expressing cells, while significantly down-regulated in PTPRO knockout cells. Conclusion: PTPRO plays ital roles in AS via promoting ox-LDL induced oxidative stress and cell apoptosis through TLR4/NF-κB pathway.

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“…TLR4 has been demonstrated to mediate myocardial ischemia reperfusion injury, maladaptive left ventricular remodeling and increased infarct size after myocardial infarction[13, 14, 24, 25]. Some research findings suggest that the activation of TLR4 signaling pathway is considered to be a promising therapeutic target for the treatment of atherosclerotic cardiovascular diseases[16, 26, 27]. In the present study, we revealed that the mRNA and protein levels of TLR4 were up-regulated after CME in rats.…”

Section: Discussionmentioning

confidence: 99%

TAK-242 Protects Against Apoptosis in Coronary Microembolization-Induced Myocardial Injury in Rats by Suppressing TLR4/NF-κB Signaling Pathway

Wang¹,

Lu²,

Sun³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Myocardial apoptosis is heavily implicated in the myocardial injury caused by coronary microembolization (CME), and toll-like receptor 4 (TLR4) is considered to be involved in this apoptotic cascade. Therefore, the present study was designed to investigate the role of TLR4/NF-κB signaling pathway regulated by TAK-242, a selective TLR4 signal transduction inhibitor, in the myocardial apoptosis after CME in rats. Methods: Forty-five rats were randomized (random number) into three groups: sham, CME and CME + TAK-242 (n = 15 per group).CME was induced by injecting polyethylene microspheres (42µm) into the left ventricular except the sham group. CME + TAK-242 group was treated with TAK-242 (2mg/kg) via the tail vein 30 minutes before CME modeling. Cardiac function was evaluated 6 hours after operation. Tissue biopsy was stained with HBFP to measure the size of micro-infarction area. TUNEL staining was used to detect myocardial apoptosis. Western blot and qPCR were used to evaluate the expression of TLR4, MyD88, NF-κB p65, p-IκBα and Cleaved caspase-3. Results: Cardiac function in the CME group and CME + TAK-242 group were significantly decreased compared with the sham group (P < 0.05) and the micro-infarction area, the apoptotic index, the expression of TLR4, NF-κB p65, p-IκBα and Cleaved caspase-3 were increased significantly (P < 0.05). Cardiac function in the CME + TAK-242 group was significantly improved compared with the CME group (P < 0.05) and the micro-infarction area, the apoptotic index, the expression of TLR4, MyD88, NF-κB p65, p-IκBα and Cleaved caspase-3 were decreased significantly (P < 0.05). Conclusions: TAK-242 can effectively improve CME-induced cardiac dysfunction by regulating TLR4/NF-κB signaling pathway and then reducing the myocardial apoptosis.

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Oxidized Low-Density Lipoprotein Promotes Macrophage Lipid Accumulation via the Toll-Like Receptor 4-Src Pathway

Cited by 22 publications

References 40 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

PTPRO Promotes Oxidized Low-Density Lipoprotein Induced Oxidative Stress and Cell Apoptosis through Toll-Like Receptor 4/Nuclear Factor κB Pathway

TAK-242 Protects Against Apoptosis in Coronary Microembolization-Induced Myocardial Injury in Rats by Suppressing TLR4/NF-κB Signaling Pathway

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