Tumor Necrosis Factor-α

Abstract

Abstract-In the Sabra rat, oxidative stress (OS) and inflammation precede the development of hypertension. Inhibition of the phagocytic NADPH oxidase attenuates the rise in blood pressure. The present study was set to identify possible priming agents for this enzyme and to test the hypothesis that the phagocytic NADPH oxidase contributes to OS and inflammation. Sabra salt-sensitive and Sabra salt-resistant rats were salt loaded or provided regular chow for 60 days with or without apocynin to inhibit NADPH oxidase. Levels of interleukin 6, tumor necrosis factor-␣, and interferon-␥ served as indices of inflammation. Extracellular and intracellular levels of the polymorphonuclear leukocyte tumor necrosis factor-␣ receptors (p55 and p75) were assessed by flow cytometry in young and adult rats. NADPH oxidase activity and expression of p47phox were measured in polymorphonuclear leukocytes and aortic rings. Malondialdehyde and carbonylated fibrinogen served as indices of OS. Inflammatory and OS indices excluding interferon-␥ were higher in the hypertensive state and reduced by apocynin. Levels of malondialdehyde and tumor necrosis factor-␣ were elevated already in the prehypertensive state. No differences were found in the levels of p75. The extracellular expression of p55 was higher in adult Sabra salt-resistant compared with Sabra salt-sensitive rats (7.46Ϯ2.2% versus 2.1Ϯ0.5%; PϽ0.05), whereas levels of the intracellular p55 were higher in adult Sabra salt-sensitive rats (3.2Ϯ2% versus 1.1Ϯ0.5%; PϽ0.05). In young normotensive rats, the extracellular levels of p55 were higher in Sabra salt-sensitive compared with Sabra salt-resistant rats (10.6Ϯ5.2% versus 2.9Ϯ1.5%; PϽ0.01). Tumor necrosis factor-␣ plays a role in activation of the polymorphonuclear leukocyte NADPH oxidase, thereby contributing to systemic OS, inflammation, and the development of hypertension in this model. We have shown that the polymorphonuclear leukocyte (PMNL) is a significant contributor to OS and inflammation in hypertensive humans and in animal models of hypertension. In pathological disorders associated with atherosclerosis and cardiovascular diseases, such as hypertension, diabetes mellitus, and end-stage renal disease, PMNLs are primed. [7][8][9] In the primed state, PMNLs are more sensitive to local or systemic stimuli because of a previous exposure to a priming agent. Hence, on encountering an additional stimulus, full cell activation occurs, resulting in a robust release of reactive oxygen species and tertiary granule contents into the bloodstream. 10 The primary source for reactive oxygen species in PMNL is the NADPH oxidase, an enzymatic complex, is composed of 3 cytosolic subunits (p40phox, p47phox, and p67phox) and 2 membrane subunits (p22phox and gp91). On cell activation, the cytosolic subunits translocate to the membrane, and the activated enzyme produces superoxide in a process known as the "respiratory burst." 11 We have reported previously that, in the Sabra rat model of hypertension, priming of PMNLs precedes the development o...

Association of TNF-α G308A gene polymorphism in essential hypertensive patients without type 2 diabetes mellitus

“…According to Bogdanski et al (2003), serum TNFα-level in EHT subjects was higher as compared to normotensive individuals, and was enhanced during the progression of EHT. Similar results in mice were also confirmed by Mazor et al (2010). These findings are still preliminary; studies on EHT and TNF-α G308A gene polymorphism is still limited (Sheu et al, 2001;Sookoian et al, 2005).…”

Essential fatty acids and their metabolites in the context of hypertension

“…15 Tumor necrosis factor-a has a function in activation of polymorphonuclear leukocyte NADPH oxidase, leading to systemic oxidative stress, inflammation and the development of hypertension. 16 In healthy middle aged and older adults, impaired endothelium-dependent dilation is decreased by a higher polymorphonuclear leukocyte count, which is mediated by reduced responsiveness to NO and increased myeloperoxidase-associated reductions in tetrahydrobiopterin and NO bioavailability. 17 How can these data explain the results reported by Begg et al 5 that DHA deficiency in the brain contributes to the development of hypertension?…”

“…26 As the brain contains all components of the renin-angiotensin system, it is likely that low brain levels of DHA and EPA could enhance the level of angiotensin II, increasing the generation of free radicals and thereby accelerating the development of hypertension. [9][10][11][12][13][14][15][16] AA, EPA and DHA can also form precursors to anti-inflammatory compounds such as lipoxins, resolvins, protectins, maresins and nitrolipids (see Figure 1 for the metabolism of essential fatty acids) that suppress leukocyte activation, inhibit free radical generation and pro-inflammatory cytokine production, enhance NO generation and exhibit potent anti-inflammatory effects. 26,27 Hence, whenever DHA (and probably other fatty acids such as AA and EPA) levels are low in the brain (especially in the hypothalamus), the production of lipoxins, resolvins, protectins, maresins and nitrolipids will be low as well, resulting in inflammation (as a result of increased production of tumor necrosis factor-a) and the induction of hypertension.…”

“…26,27 Hence, whenever DHA (and probably other fatty acids such as AA and EPA) levels are low in the brain (especially in the hypothalamus), the production of lipoxins, resolvins, protectins, maresins and nitrolipids will be low as well, resulting in inflammation (as a result of increased production of tumor necrosis factor-a) and the induction of hypertension. 14,16 EPA and possibly DHA suppress the production of leptin, 28 which has pro-inflammatory effects 29 similar to those of angiotensin II. This may explain the increased plasma leptin levels noted by Begg et al 5 and the function of leptin in hypertension because hypertension is a low-grade systemic-inflammatory condition.…”

TNF-α in the cardiovascular system: from physiology to therapy

“…44 NOX catalyze the transfer of electrons from NADPH to molecular oxygen, resulting in generation of superoxide. Other potential sources of TNF-α-induced vascular superoxide production include ceramide-activated protein kinase, xanthine oxidase, 45 lipoxygenase, mitochondrial oxidase, and uncoupled eNOS.…”