35 Fetuin-A and toll-like receptor 4 regulate vascular function: role of Nox1

Heart ◽  
2015 ◽  
Vol 101 (Suppl 6) ◽  
pp. A12.1-A12
Author(s):  
KB Neves ◽  
RAM Lopes ◽  
S Leckerman ◽  
A Strembitska ◽  
C Jenkins ◽  
...  
Keyword(s):  
Vascular Function ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Fetuin A

Abstract P083: Fetuin-a Induces Vascular Dysfunction Through Toll-like Receptor 4 And Nox1/4 Activation

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Karla B Neves ◽  
Rheure A Lopes ◽  
Anastasiya Strembitska ◽  
Ross Hepburn ◽  
Wendy Beattie ◽  
...  
Keyword(s):  
Vascular Function ◽  
Molecular Mechanisms ◽  
Vascular Dysfunction ◽  
Convincing Evidence ◽  
Ros Production ◽  
Toll Like Receptor ◽  
Vascular Effects ◽  
Toll Like Receptor 4 ◽  
Fetuin A ◽  
Wky Rats

Although studies demonstrate an important role for fetuin-A (FetA) in the inhibition of vascular calcification, convincing evidence suggests that fetuin-A is also involved in insulin resistance, inflammation and cardiovascular damage. The present study seeks to unravel FetA vascular effects and associated molecular mechanisms, focusing on oxidative stress and toll-like receptor 4 (TLR4). Vascular function studies were performed in mesenteric resistance arteries from WKY rats, wild-type, Nox1 KO, Nox4 KO and Ang II-dependent hypertensive mice (LinA3) and rat aortic endothelial cells (RAEC). ROS production (chemiluminescence, Amplex Red, ELISA) and pro-inflammatory markers expression (RT-PCR) were measured in VSMCs from WKY rats and RAEC. FetA impaired endothelium-dependent (LogEC50 7.320±0.08 M vs control 8.025±0.06) and endothelium-independent vasorelaxation (LogEC50 6.48±0.19 M vs control 7.38±0.12), p<0.05; effects blocked by tempol (superoxide dismutase mimetic), Nox1 inhibitor, ML171, and TLR4 inhibitor, CLI095. We did not observe any changes in contraction. FetA increased ROS production (62%) and peroxynitrite levels (158%) in VSMCs; while in RAEC, FetA increased ROS production (105%) followed by a decrease in H2O2 (62%) levels (p<0.05 vs control). FetA-induced effects on ROS were inhibited by ML171 and GKT137831 (Nox1/Nox4 inhibitor), as well as CLI095. Vascular dysfunction in arteries from Nox1 and Nox4 KO mice was unaffected by FetA. Activation of the FetA/TLR4/Nox axis led to an increase in IL-1β (190%), Il-6 (124%) and RANTES mRNA expression(116%) in RAEC, p<0.05 vs control. FetA enhanced vascular dysfunctionin LinA3 mice. Together, these results suggest that FetA through TLR4/Nox1 and 4-derived ROS leads to vascular dysfunction and inflammation, which may play an important role in the development of vascular injury during hypertension.

Abstract 099: Fetuin-A and Toll-like Receptor 4 Regulate Vascular Function: Role of Nox1

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Augusto C Montezano ◽  
Karla B Neves ◽  
Rheure A Lopes ◽  
Susan Leckerman ◽  
Anastasiya Strembitska ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Protein Oxidation ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Rho Kinase ◽  
Mesenteric Arteries ◽  
Ros Production ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Fetuin A

Fetuin-A (FetA) regulates calcium and phosphate homeostasis. It is also an agonist to toll-like receptor 4 (TLR4) and is related to insulin resistance and inflammation. FetA has also been associated with endothelial dysfunction, which is regulated by oxidative stress. Mechanisms whereby FetA influences vascular function are unknown. We hypothesized that FetA through TLR4 and ROS production induces vascular dysfunction. Mesenteric arteries and vascular cells from WKY rats were studied. Vascular function was analysed by wire myography in the presence or absence of FetA (50 ng/mL) and/or CLI095 (CLI - 10-6M - TLR4 inhibitor). Levels of reactive oxygen species (ROS) were measured by chemiluminescence, Amplex Red (H2O2) and ELISA (nitrotyrosine) Protein oxidation and levels were measured by immunoblotting. WKY vessels exposed to FetA were less sensitive to acetylcholine (Ach)-induced and sodium nitroprusside (SNP)-induced relaxation, while sensitivity to phenylephrine was increased by FetA; an effect blocked by N-acetylcysteine (antioxidant) and ML171 (Nox1 inhibitor). Inhibition of TLR4 blocked FetA effects on endothelial-dependent relaxation and contraction, but not on endothelial-independent relaxation. FetA increased ROS production (131±49.2%), but decreased H2O2 intracellular levels (63±14%) in endothelial cells (EC) (vs. veh, p<0.05); an effect blocked by CLI095. ROS production (66±12.2%), as well as, H2O2 (45±8%) and ONOO- (105±31.6%) levels, were increased by FetA in VSMCs (vs. veh, p<0.05). Protein oxidation was increased by FetA in VSMCs (103±26% vs. veh, p<0.05). In EC, eNOS inactivation (136±38%) and JNK activation (84±5%) were increased by FetA (vs. veh, p<0.05). In VSMCs, Rho kinase activity was increased (200±25% vs. veh, p<0.05) at 30 min; while myosin light chain (MLC) activation was only increased (25±3.56% vs. veh, p<0.05) at 15 min. In summary, FetA influences vascular function through Nox1-ROS dependent mechanisms. FetA-induced endothelial dysfunction and contractile responses involve TLR4. Our findings identify a novel system whereby FetA differentially influences vascular function through Nox1-ROS and TLR4. Vascular responses to FetA may depend on the specific pathway activated.

Abstract P340: Molecular Mechanisms of Fetuin-a-induced Vascular Dysfunction and Inflammation: Role of Oxidative Stress and Toll-like Receptor 4

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Augusto C Montezano ◽  
Delyth Graham ◽  
Rhian M Touyz
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Endothelial Cells ◽  
Vascular Function ◽  
Cell Metabolism ◽  
Ros Production ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Fetuin A ◽  
Tlr4 Activation

Fetuin-A (FetA) is an endogenous agonist to toll-like receptor 4 (TLR4) and regulates insulin resistance and inflammation. FetA has been associated with endothelial dysfunction during metabolic diseases. Exact mechanisms whereby FetA influences vascular function in pathological conditions remain unknown, but we demonstrated that FetA regulates vascular function by Nox1 and TLR4 activation. Here we hypothesized that FetA, through changes in cell metabolism and activation of TLR4-Nox1 axis induces ROS formation and inflammation in hypertension. Normotensive (WKY) and hypertensive (SHRSP) vascular cells, as well as human microvascular endothelial cells, were stimulated with FetA (50 ng/mL). ROS production was measured by lucigenin and Amplex red, while gene expression was assessed by qPCR. FetA increased ROS production (131±49.2%), decreased H 2 O 2 intracellular levels (63±14%) and increased gene levels of IL6 (2 fold), IL1β (1 fold), RANTES (1 fold) and MMP2/9 (2 fold) in rat endothelial cells ( vs. veh, p<0.05); all effects were blocked by TLR4 inhibitor (CLI095) and Nox1 inhibitor (ML171). FetA increased JNK (184±19%), but not p38 MAPK, activation in endothelial cells. In VSMCs, FetA-induced TLR4-dependent ROS generation was similar in WKY (136±9%) and SHRSP (144±14%) (p<0.05 vs veh). However, while IL6 gene expression was increased by FetA in WKY (4 fold) and SHRSP (0.5 fold), IL-1β gene levels were only increased by FetA in SHRSP (1 fold) derived VSMCs (p<0.05). CLI095 inhibited FetA effects on IL6 expression; however, TLR4 inhibition did not block FetA effects on IL-1β gene levels. In human endothelial cells, FetA increased ROS levels, was inhibited by CLI095 and a glucose-6-phosphate dehydrogenase (G6PD) inhibitor (6-aminonicotinamide), suggesting that FetA effects may be related to control of cell metabolism. In conclusion, FetA seems to regulate ROS and pro-inflammatory responses by TLR4, Nox1 and G6PD in endothelial cells. In VSMCs, FetA effects on oxidative stress and markers of cell injury are partially dependent on TLR4 activation and may involve other molecular partners.

scholarly journals Detrimental Role of Heat Shock Protein 60&70 and Toll-like Receptor 4 in Skeletal Muscle Ischaemia In Vitro

2013 ◽  
Vol 57 (5) ◽  
pp. 77S
Author(s):  
Ali Navi ◽  
Rebekah Yu ◽  
Xu Shi-Wen ◽  
Sidney Shaw ◽  
George Hamilton ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 60 ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Muscle Ischaemia

Contrasting effects of the Toll-like receptor 4 in determining ovarian follicle endowment and fertility in female adult mice

Zygote ◽  
2021 ◽  
pp. 1-7
Author(s):  
Júlio Panzera Gonçalves ◽  
Breno Augusto Magalhães ◽  
Paulo Henrique Almeida Campos-Junior
Keyword(s):  
Ovarian Follicle ◽  
Cumulus Cells ◽  
Toll Like Receptor ◽  
Female Reproduction ◽  
Toll Like Receptor 4 ◽  
Genetic Ablation ◽  
Adult Mice ◽  
Cumulus Oocyte Complex ◽  
Estrous Cyclicity

Abstract Toll-like receptor 4 (TLR4) is best known for its role in bacteria-produced lipopolysaccharide recognition. Regarding female reproduction, TLR4 is expressed by murine cumulus cells and participates in ovulation and in cumulus–oocyte complex (COC) expansion, maternal–fetal interaction and preterm labour. Despite these facts, the role of TLR4 in ovarian physiology is not fully understood. Therefore, the aim of the present study was to investigate the effects of TLR4 genetic ablation on mice folliculogenesis and female fertility, through analysis of reproductive crosses, ovarian responsiveness and follicular quantification in TLR4−/− (n = 94) and C57BL/6 mice [wild type (WT), n = 102]. TLR4-deficient pairs showed a reduced number of pups per litter (P = 0.037) compared with WT. TLR4−/− mice presented more primordial, primary, secondary and antral follicles (P < 0.001), however there was no difference in estrous cyclicity (P > 0.05). A lower (P = 0.006) number of COC was recovered from TLR4−/− mice oviducts after superovulation, and in heterozygous pairs, TLR4−/− females also showed a reduction in the pregnancy rate and in the number of fetuses per uterus (P = 0.007) when compared with WT. Altogether, these data suggest that TLR4 plays a role in the regulation of murine folliculogenesis and in determining ovarian endowment. TLR4 deficiency may affect ovulation and pregnancy rates, potentially decreasing fertility, therefore the potential side effects of its blockade have to be carefully investigated.

Abstract 1766: Diet-Induced Obesity Causes Inflammation by Activating Toll-Like Receptor 4 Signaling and Downregulates AMPK in Heart

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Hwi Jin Ko ◽  
Dae Young Jung ◽  
Zhexi Ma ◽  
Jason K Kim
Keyword(s):  
Glucose Metabolism ◽  
Whole Body ◽  
Chow Diet ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Myocardial Glucose Metabolism ◽  
Cardiac Inflammation ◽  
Protein Levels ◽  
Diet Induced Obesity

Increasing evidence implicates the role of inflammation in diabetes and complications. Macrophages are shown to infiltrate adipose tissue in obesity, and inflammatory cytokines alter glucose metabolism in peripheral organs. Male C57BL/6 mice were fed high-fat diet (HFD; 55% fat by calories) or chow diet for 6 weeks, and heart samples were taken for analysis (n = 5~7). Chronic HFD increased whole body fat mass, measured by 1 H-MRS, by 3-fold, and elevated plasma IL-6 and TNF-α levels by 40%. Diet-induced obesity caused inflammation in heart and increased macrophage-specific CD68 levels by 5-fold (Fig. 1) (* P < 0.05 vs Chow). Diet-induced cardiac inflammation was associated with significant increases in toll-like receptor 4 (TLR4) and MyD88 levels in heart (Fig. 2). HFD also increased cardiomyocyte SOCS3 levels by more than 3-fold (Fig. 3). Myocardial glucose metabolism was measured using intravenous injection of 2-[ 14 C]deoxyglucose in awake mice (n = 6). Chronic HFD reduced myocardial glucose uptake by 50%, and this was associated with significant reductions in total GLUT4 and GLUT1 protein levels. Further, Thr 172 phosphorylation of AMPK, a critical regulator of energy balance, was markedly reduced in heart following HFD (Fig. 4). These results demonstrate that diet-induced obesity causes macrophage infiltration and inflammation in heart by increasing TLR4 signaling in cardiomyocytes. Similar to the effects of inflammation on peripheral glucose metabolism, diet-induced cardiac inflammation reduced myocardial glucose metabolism by downregulating AMPK and GLUT protein levels. Thus, our findings underscore an important role of inflammation in diabetic heart.

Role of the toll-like receptor 4 polymorphism Asp299Gly in longevity and myocardial infarction in German men

2007 ◽  
Vol 128 (5-6) ◽  
pp. 409-411 ◽  
Author(s):  
Almut Nebel ◽  
Friederike Flachsbart ◽  
Arne Schäfer ◽  
Michael Nothnagel ◽  
Susanna Nikolaus ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4

scholarly journals The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Monica Molteni ◽  
Sabrina Gemma ◽  
Carlo Rossetti
Keyword(s):  
Tissue Injury ◽  
Sterile Inflammation ◽  
Research Progress ◽  
Toll Like Receptor ◽  
Proinflammatory Response ◽  
Toll Like Receptor 4 ◽  
The Family ◽  
Tlr4 Activation ◽  
Molecular Patterns

Toll-like receptor 4 (TLR4) belongs to the family of pattern recognition receptors (PRRs). They are highly conserved receptors that recognize conserved pathogen-associated molecular patterns (PAMPs), thus representing the first line of defense against infections. TLR4 has been long recognized as the sensing receptor for gram-negative lipopolysaccharide (LPS). In addition, it also binds endogenous molecules produced as a result of tissue injury. Hence, TLR4 represents a key receptor on which both infectious and noninfectious stimuli converge to induce a proinflammatory response. TLR4-mediated inflammation, triggered by exogenous or endogenous ligands, is also involved in several acute and chronic diseases, having a pivotal role as amplifier of the inflammatory response. This review focuses on the research progress about the role of TLR4 activation in infectious and noninfectious (e.g., sterile) inflammation and the effects of TLR4 signaling in some pathological conditions.

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