Pivotal role of TNF-α in vascular dysfunction

Even though numerous risk factors, such as physical inactivity, smoking and over-nutrition, appear to contribute to the development of vascular dysfunction, normal aging is also an independent factor in the aetiology of cardiovascular diseases. There is evidence, however, that those seemingly diverse processes converge on modulating TNF-α signalling to lead to the generation of dysfunctional endothelium and the onset of vascular diseases. TNF-α induces the gene expression of various inflammatory cytokines and chemokines, either dependently or independently of the activation of transcriptional factors, such as NF-κB and AP-1 (activator protein 1). This TNF-α-mediated signalling initiates and accelerates atherogenesis, thrombosis, vascular remodelling, vascular inflammation, endothelium apoptosis, vascular oxidative stress and impaired NO bioavailability, which contribute to the blunted vascular function. Dietary supplements and exercise favourably reduce the risk of vascular dysfunction by inhibiting TNF-α production and (or) TNF-α-mediated signalling. Risk factors in orange demonstrate those factors that converge on TNF-α to induce vascular dysfunction. Factors in green denote those that protect against vascular damage mediated by TNF-α expression and signalling. TNF-α-induced pathophysiological conditions related to vascular function are shown in blue. Both vascular risk factors and protective factors affect the regulation of vascular functions by modulating TNF-α production and downstream signalling. MCP-1, monocyte chemoattractant protein-1; MMP, matrix metalloproteinase; TF, tissue factor.

Tumor necrosis factor, abbreviated as TNF, is a protein that your white blood cells make in response to inflammation or infection throughout your body. Sometimes TNF can be beneficial to your body by heightening your immune response. TNF can also be harmful, as the substance might activate other bodily reactions, such as the growth of cancer cells, according to Breast Cancer Choices. Certain herbal remedies may help block TNF, which might improve your health.

Figure 2

Role of TNF-α in endothelial dysfunction

TNF-α reduces the production of NO through the inhibition of the enzyme activities of ASS and eNOS, and enhances the removal of NO through the increase in NADPH-dependent O2•− production to react with NO to form ONOO. As a consequence, TNF-α decreases the bioavailability of NO to induce relaxation of smooth muscle in the vasculature. TNF-α also diminishes EETs, one of the candidate EDHFs, via the inhibition of cytochrome P450 (CYP 450) enzyme activity. AA, arachidonic acid.

TNF-α AND HIGH-FAT AND HIGH-CARBOHYDRATE DIETS

The effects of over-nutrition on endothelial dysfunction in healthy subjects and subjects with dyslipidaemia, the metabolic syndrome and diabetes have been examined in many studies. Endothelial function was markedly impaired by a high-fat meal that caused an acute hypertriacylglycerolaemia. This impairment was evident in patients with dyslipidaemia with baseline hypertriacylglycerolaemia, but not in controls with normotriacylglycerolaemia [80]. Compared with the control group, subjects with metabolic syndrome had reduced endothelial function, as assessed using the L-arginine test, and higher circulating levels of TNF-α. Following the high-fat meal, both triacylglycerol and TNF-α levels increased more in subjects with the metabolic syndrome than in normal subjects, whereas endothelial function decreased more in subjects with the metabolic syndrome [81]. Moreover, in healthy subjects, the high-fat meal increased plasma levels of TNF-α, IL-6, ICAM-1 and VCAM-1 (vascular cell adhesion molecule-1), while the high-carbohydrate meal had no effects in these subjects. In patients with diabetes, both meals significantly increased cytokine and adhesion molecule levels, but the increase lasted longer following the high-fat meal [82]. On the basis of the significant relationship between increases in TNF-α levels and decreases in endothelial function in subjects with the metabolic syndrome and diabetes [81], the mechanisms of TNF-α-induced endothelial dysfunction following high-energy diets has been extensively studied at the molecular and cellular levels. Intraluminal butter administration significantly increased TNF-α expression in lamina proprial macrophage and lymphocyte adherence to intestinal microvessels, accompanied by increases in the expression levels of ICAM-1, MAdCAM-1 (mucosal adhesion cell adhesion molecule-1) and VCAM-1. Furthermore, anti-TNF-α treatment attenuated the enhanced expression of adhesion molecules induced by butter administration [83]. Therefore high-energy diets may cause endothelial dysfunction, as well as potentiate TNF-α-mediated EC injury [84]. Reducing saturated fat and dietary cholesterol intake and avoiding excess calories remains the cornerstone of the dietary approaches to decrease the risk of vascular diseases.

ROLE OF EXERCISE IN CARDIOVASCULAR DISEASE

Pro-inflammation events, such as the increases in TNF-α, CRP (C-reactive protein), IL-6 and resistin, appear to produce their harmful effects, at least in part, by inducing endothelial dysfunction and also by decreasing endothelial NO generation. NO inhibits platelet adherence and aggregation, suppresses vasoconstriction, reduces the adherence of leucocytes to the endothelium and suppresses the proliferation of VSMCs (vascular smooth muscle cells) [85]. Of these pro-inflammatory cytokines, TNF-α is a key player in systemic low-level inflammation through stimulating the expression of adhesion molecules on ECs and thereby inducing endothelial dysfunction [85,86]. TNF-α is a strong biological driver of the metabolic syndrome, which is characterized by abdominal obesity, hypertension, a reduced level of HDL, elevated triacylglycerols and high-fasting glucose, and constitutes an important risk factor in atherosclerosis and Type 2 diabetes [86]. Keller et al. [87] have reported that TNF-α overexpression returned to normal levels after 1 h of acute swimming exercise in TNFR (TNF receptor)-knockout mice. In addition, chronic exercise appears to suppress pro-inflammatory factors, such as TNF-α, CRP and IL-6, and augment anti-inflammatory factors, including IL-4, IL-10, TGF-β (transforming growth factor-β) and adiponectin, even though these results showed discrepancies according to the modes, intensity and time duration of exercise [86,8890]. Therefore the anti-inflammatory effects of exercise may offer protection against TNF-α-induced insulin resistance and the secondary development of cardiovascular dysfunction. In summary, regular exercise contributes to the prevention of cardiovascular dysfunction by controlling traditional cardiovascular risk factors, including HDL- and LDL (low-density lipoprotein)-cholesterol, improving antioxidant factors, such as SOD (superoxide dismutase) and glutathione peroxidase, elevating the anti-inflammatory effect and suppressing TNF-α, which is the main pro-inflammatory cytokine

http://www.clinsci.org/content/116/3/219

Turmeric

Cook with turmeric to block TNF. Turmeric is an herb commonly used in curries and other Indian dishes and is available in the spice aisle of most supermarkets. Turmeric contains a chemical called curcumin, which is traditionally used to control inflammation. The spice may also play a role in inhibiting TNF, according to the Multiple Sclerosis Encyclopaedia. Curcumin is also available in capsule form if you do not like the taste of turmeric.

Milk thistle

Take milk thistle to inhibit TNF. Milk thistle is a plant used mainly to protect against and treat liver disease. Silymarin, a main component of milk thistle, has antioxidant and anti-flammatory properties. A 1999 article in the Journal of Immunology reports that these properties can also block TNF from activating a nuclear transcription factor in the body that controls inflammation and the development of cancer cells. The University of Maryland Medical Center recommends 280 to 450 mg of milk thistle daily for adults.

Nettle leaf extract

Ask your doctor about taking stinging nettle leaf extract to inihibit TNF. This herbal remedy’s effect on colitis, a chronic inflammatory disease, was investigated by German and Swiss researchers. The results, reported in the January 2005 issue of the International Journal of Colorectal Disease, showed that concentrations of TNF were lower in animals who were given nettle leaf extract than those who were not treated with herbal remedies. Stinging nettle leaves can be brewed into a a tea or taken as a fluid extract.

http://www.livestrong.com/article/145241-how-to-block-tnf-with-herbal-remedies/

Pentoxifylline

Pentoxifylline is effective mainly because it blocks TNF.

Acetyl-L-carnitine

Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy.

Citruline Malate

TNF-α decreases the bioavailability of NO to induce relaxation of smooth muscle through inhibition Citrulline-NO Cycle.

CoQ10

CoQ10 is effective because it protects and enhances cellular mitochondria which provide life energy to the tissues.

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