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.

Abstract P222: Ablation of Tool Like Receptor-4 Mitigates Blood Pressure Response During Hyperhomocysteinemia

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Nevena Jeremic ◽  
Anastasia Familtseva ◽  
Pankaj Chaturvedi ◽  
George H Kunkel ◽  
Suresh C Tyagi
Keyword(s):  
Blood Pressure ◽  
Endothelial Cell ◽  
Mitochondrial Dysfunction ◽  
Vascular Remodeling ◽  
Diastolic Pressure ◽  
Mitochondrial Fission ◽  
Cell Loss ◽  
Mitochondrial Fusion ◽  
Endothelial Cell Loss ◽  
Immune System Activation

Background: A significant number of studies have shown a positive correlation between Hcy plasma levels and hypertension. On the other hand pathogen recognition receptor, and in particular TLR-4 is a foreign antigen sensor that plays role in innate immune system activation and has recently gained a significant attention in the field of hypertension. Mitochondrial dysfunction and mitochondria-dependent apoptosis have been shown to promote endothelial cell loss leading to endothelial dysfunction that contributes to pathogenesis of hypertension. These events induce mitochondrial dysfunction characterized by excessive mitochondrial fission and mitochondrial apoptosis contributing to vascular remodeling followed by hypertension. Objective: The objective of this study is to define the mechanisms of homocysteine effect on aortic wall that promote vascular remodeling and hypertension and explore the role of TLR-4 mutation in alleviation of homocysteine negative effects. Methods: For this study we used 5 groups of mice: C57BL/6J, C3H/HEouJ, CBS+/-; C3H/HeJ, and CBS+/-/C3H. For further analysis we used isolated aorta and collected blood. Blood pressure was recorded using noninvasive tail cuff method. Effects of hyperpolarization factor and endothelial-dependent vasodilator on aorta contractility were also performed. We checked expression of mitochondrial fusion and fission proteins, antioxidant markers and expression of collagen/elastin fragments. Results: Data showed that there were increased values of systolic and diastolic pressure in CBS+/- mice (DP: 127.06±18.24; SP: 159.59±15.84) and C3H/HeJ mice had decreased levels of in comparing to other groups (DP: 55.43±16.19; SP: 110.04±5.90). The response to hyperpolarization factor and endothelial-dependent vasodilator were blended in CBS+/- aorta, however mitigated in CBS+/-/C3H. Fusion and fission ratio (Mfn2/DRP1) were increased in C3H/HeJ mice (1.53±0.08) and mostly decreased in CBS+/- mice (0.42±0.05) compering to other groups. Conclusion: These findings indicate the prevalence of mitochondrial fission over mitochondrial fusion in HHcy may explain possible endothelial cell loss and dysfunction followed by collagen accumulation that contributes to vascular remodeling.

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.

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.

Abstract P133: Mitochondrial- Dependent Apoptosis in Arterial Remodeling: Link to Hypertension

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Anastasia Familtseva ◽  
Anuradha Kalani ◽  
Pankaj Chaturvedi ◽  
Naira Metreveli ◽  
Suresh C Tyagi
Keyword(s):  
Blood Pressure ◽  
Endothelial Cell ◽  
Mesenteric Artery ◽  
Caspase 3 ◽  
Mitochondrial Fission ◽  
Cell Loss ◽  
Arterial Remodeling ◽  
Endothelial Cell Loss ◽  
Caspase 9 ◽  
C3h Mice

Hyperhomocysteinemia (HHcy) has been observed to promote hypertension through endothelial dysfunction and vascular remodeling, but the mechanisms are unclear. Previously, we showed that elevated homocysteine levels disturbed mitochondrial dynamics facilitating excessive mitochondrial fission with consequent endothelial cell loss and collagen deposition in the mesenteric artery. In the present study, we hypothesize that HHcy-induced excessive mitochondrial fission promotes mitochondrial apoptosis through Bax activation that up- regulates downstream apoptotic proteases (Caspase-9, Caspase-3), causing endothelial cell loss and arterial remodeling that predispose to hypertension. To test this hypothesis, we used 12 week old C57BL/6J mice (WT) as a control; Cystathionine-β-synthase deficient mice (CBS+/-) with genetic HHcy; C3H/HeJ (C3H) mice, that are resistant to oxidative stress and CBS+/-/C3H mice. Blood pressure and vascular reactivity measurements, western blotting (Caspase-9 and Caspase-3), q-PCR (Bax, Bcl-2), immunohistochemistry (cleaved Caspase-3) and TUNEL assay were used in this study. Blood pressure values were up-regulated in CBS+/- mice (diastolic: 118.4 ± 9.8 mmHg; systolic: 153.9 ± 12.7 mmHg; mean: 130 ± 10 mmHg) compared to WT mice (diastolic: 101 ± 15 mmHg; systolic: 139 ± 10 mmHg; mean: 113 ± 14 mmHg). Interestingly, blood pressure values were decreased in C3H mice (diastolic: 74.8 ± 6.5 mmHg; systolic: 118.6 ± 9 mmHg; mean: 89 ± 7 mmHg) compared to control (diastolic: 96 ± 7 mmHg; systolic: 143.4 ± 2.4 mmHg; mean: 111.4 ± 5.5 mmHg). q-PCR showed 11 fold up-regulation of Bax mRNA expression in the mesenteric artery of CBS+/- mice compared to control. Western Blotting validated two- fold increase of Caspase-9 and Caspase-3 protein expressions in the mesenteric artery of CBS+/- mice compared to WT mice. TUNEL assay further indicated the presence of DNA fragments in the mesenteric artery of CBS+/- mice. In conclusion, our data suggested that HHcy-induced mitochondrial fission promotes Bax activation followed by mitochondrial apoptosis with activation of downstream proteases (Caspase-9, Caspase-3), leading to endothelial cell loss and arterial remodeling that contributes to hypertension.

Sign in / Sign up

Export Citation Format

Share Document