Role of platelets in NOX2 activation mediated by TNFα in heart failure

Abstract

Tumor necrosis factor (TNF) α may contribute to the deterioration of cardiovascular function in heart failure (HF) through various mechanisms, including the generation of reactive oxygen species (ROS). NADPH oxidase is the major source of ROS in the vascular system, but the interplay between TNFα and NADPH oxidase activation is elusive. As platelets possess NADPH oxidase enzyme, they represent an important tool to investigate the interplay between NADPH oxidase and TNFα in patients with HF. Serum gp91phox (NOX2), the catalytic core of NADPH oxidase, and serum TNFα were measured in 120 HF patients and in 60 healthy subjects. Compared with healthy subjects, HF patients had higher blood levels of NOX2 and TNFα with a progressive increase from NYHA I to NYHA IV classes. NOX2 levels in blood were independently associated with TNFα in HF patients. An in vitro study, performed on platelets from a subgroup of HF patients, shows that TNFα, at concentrations commonly found in HF patients' peripheral circulation, activates platelet NOX2. Thus, TNFα increases ROS production and the extracellular levels of NOX2. These phenomena are inhibited by the NOX2-specific blocking peptide gp91ds-tat. The study provides evidence that circulating NOX2, as well as the activation of NOX2 on platelets, is increased in HF likely as a consequence of the underlying inflammatory process.

QSYQ Attenuates Oxidative Stress and Apoptosis Induced Heart Remodeling Rats through Different Subtypes of NADPH-Oxidase

“…There is evidence indicating that the expressions of NOX2 and NOX4 are markedly changed, accompanied by the activation of apoptosis [23]. Consistent with previous studies, here we found changed expressions of SOD and MDA in HF model, suggesting that induction of oxidative stress occurred during HF after MI [24]. Moreover, the two isoforms of NADPH oxidases were believed to cause apoptosis by inducing ROS [25].…”

Altered redox status in the blood of psoriatic patients: involvement of NADPH oxidase and role of anti-TNF-α therapy

“…17 It is important to note that TNF-α also acts as a potent inducer of ROS generation through impairment of mitochondrial biogenesis and activation of NADPH oxidase. 8,[18][19][20][21][22][23] Taken together, these data allow us to speculate that the immune system and the redox system might in some way interact synergistically, such that both mechanisms might be relevant in the pathogenesis of psoriasis.…”

“…TNF-α has been also shown to activate Nox1 NADPH oxidase in mouse fibroblasts when cells undergo necrosis. 22 Finally, an in vitro study carried out by Cangemi et al, 23 which was carried out in platelets from a subgroup of heart failure patients, showed that TNF-α (at concentrations commonly found in the peripheral circulation of heart failure patients) activates platelet NOX2. Thus, TNF-α increases ROS production and extracellular levels of NOX2.…”

“…These findings agree with those reported by other authors, who showed that activity of NADPH oxidase can be regulated by TNF-α. 8,[18][19][20][21][22][23] Indeed, a pronounced morphological change and increase in ROS production in mitochondria following TNF-α treatment has recently been shown in insulinresistant 3T3-L1 adipocytes. 19 In another study, human aortic smooth muscle cells and embryonic kidney cells treated with TNF-α displayed increased superoxide production, due to upregulated expression of NOX4 and NOX2 isoforms of NADPH oxidase, respectively.…”

Clinical Application of NOX Activity and Other Oxidative Biomarkers in Cardiovascular Disease: A Critical Review

“…Such interplay is useful to explain the tendency to venous and artery thrombosis in clinical settings, such as heart failure, cirrhosis, anoxia-reoxygenation, atrial fibrillation, and diabetes, all of which are characterized by the up-regulation of NOX2 and the over-expression of isoprostane (10,11,(20)(21)(22).…”