scholarly journals Loss of toll-like receptor 4 ameliorates cardiovascular dysfunction in aged mice

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Huan Liu ◽  
Shujuan Chu ◽  
Zhilin Wu
Keyword(s):  
Oxidative Stress ◽  
Insulin Sensitivity ◽  
Inflammatory Responses ◽  
Cardiac Performance ◽  
Dependent Manner ◽  
Vascular Relaxation ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Aged Mice ◽  
And Oxidative Stress

Abstract Background Toll-like receptor 4 (TLR4) is a pattern recognition receptor of the innate immune system. TLR4 contributes to many aging-related chronic diseases. However, whether TLR4 is involved in cardiovascular injury during the aging process has not been investigated. Methods The effects of TLR4 on the cardiovascular system of aged mice were investigated in TLR4−/− mice. An intraperitoneal glucose tolerance test (IPGTT) and insulin sensitivity test (IST) were conducted to evaluate global insulin sensitivity. Echocardiography was used to measure cardiac structure and performance. An isolated artery ring assay was used to measure the vasodilator function of the thoracic aorta. The inflammatory response was reflected by the serum concentration of cytokines. Results TLR4 expression increased in the hearts and aortas of mice in an age-dependent manner. Loss of TLR4 increased insulin sensitivity in aged mice. Moreover, loss of TLR4 improved cardiac performance and endothelium-dependent vascular relaxation in aged mice. Importantly, the increases in serum inflammatory cytokines and oxidative stress in the heart and aorta were also inhibited by TLR4 deficiency. Conclusion In summary, loss of TLR4 improved cardiac performance and endothelium-dependent vascular relaxation in aged mice. The reduced inflammatory responses and oxidative stress may be the reason for the protective effects of TLR4 deficiency during aging. Our study indicates that targeting TLR4 is a potential therapeutic strategy for preventing aging-related cardiovascular disease.

scholarly journals Toll-Like Receptor 4 Promotes NO Synthesis by Upregulating GCHI Expression under Oxidative Stress Conditions in Sheep Monocytes/Macrophages

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Shoulong Deng ◽  
Kun Yu ◽  
Baolu Zhang ◽  
Yuchang Yao ◽  
Zhixian Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Inflammatory Responses ◽  
Gram Negative Bacteria ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Gram Negative ◽  
Transgenic Sheep ◽  
And Oxidative Stress

Many groups of Gram-negative bacteria cause diseases that are harmful to sheep. Toll-like receptor 4 (TLR4), which is critical for detecting Gram-negative bacteria by the innate immune system, is activated by lipopolysaccharide (LPS) to initiate inflammatory responses and oxidative stress. Oxidation intermediates are essential activators of oxidative stress, as low levels of free radicals form a stressful oxidative environment that can clear invading pathogens. NO is an oxidation intermediate and its generation is regulated by nitric oxide synthase (iNOS). Guanosine triphosphate cyclohydrolase (GCHI) is the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis, which is essential for the production of inducible iNOS. Previously, we made vectors to overexpress the sheepTLR4gene. Herein, first generation (G1) of transgenic sheep was stimulated with LPSin vivoandin vitro, and oxidative stress and GCHI expression were investigated. Oxidative injury caused by TLR4 overexpression was tightly regulated in tissues. However, the transgenic (Tg) group still secreted nitric oxide (NO) when an iNOS inhibitor was added. Furthermore, GCHI expression remained upregulated in both serum and monocytes/macrophages. Thus, overexpression of TLR4 in transgenic sheep might accelerate the clearance of invading microbes through NO generation following LPS stimulation. Additionally, TLR4 overexpression also enhances GCHI activation.

Ablation of toll-like receptor 4 mitigates cardiac mitochondrial dysfunction in hyperhomocysteinemia

2017 ◽  
Vol 95 (11) ◽  
pp. 1369-1375 ◽  
Author(s):  
Nevena Jeremic ◽  
Gregory J. Weber ◽  
Suresh C. Tyagi
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cell ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Fission ◽  
Cell Loss ◽  
Toll Like Receptor ◽  
Endothelial Cell Loss ◽  
Toll Like Receptor 4 ◽  
Immune Response Pathway ◽  
And Oxidative Stress

Hyperhomocysteinemia (HHcy) is a risk factor for adverse cardiovascular events; however, the mechanism for development of this disease is still unknown. Toll-like receptor 4 (TRL4) is a molecule involved in the immune response pathway and is quickly becoming a receptor of interest in the field of hypertension. In this study, we hypothesized that ablation of TLR4 mitigates cardiac mitochondrial dysfunction in a model of HHcy. Five strains of mice (C57BL/6J, CBS+/−, C3H, CBS+/−/C3H, and C3H/HeOuJ) 10–12 weeks old were utilized. We found that HHcy causes heart hypertrophy and promotes oxidative stress while mice with HHcy and inactivated TLR4 showed significant improvement in examined parameters. A dominance of endothelial cell mitochondrial fission over mitochondrial fusion in HHcy and oxidative stress was observed, which may explain the endothelial cell loss and dysfunction that contributes to inward cardiac remodeling.

Toll-like receptor 4 promotes high glucose-induced catabolic and inflammatory responses in chondrocytes in an NF-κB-dependent manner

Life Sciences ◽  
2019 ◽  
Vol 228 ◽  
pp. 258-265 ◽  
Author(s):  
Hongzhi Liang ◽  
Huajun Wang ◽  
Leifeng Luo ◽  
Shuxin Fan ◽  
Li Zhou ◽  
...  
Keyword(s):  
High Glucose ◽  
Inflammatory Responses ◽  
Dependent Manner ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

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

2017 ◽  
Vol 42 (2) ◽  
pp. 495-505 ◽  
Author(s):  
Caihong Liang ◽  
Xiaochen Wang ◽  
Jianping Hu ◽  
Xiaoqing Lian ◽  
Tiantian Zhu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Apoptosis ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Toll Like Receptor ◽  
Oxidized Low Density Lipoprotein ◽  
Toll Like Receptor 4

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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