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

Tumor necrosis factor (TNF) \u3b1 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 TNF\u3b1 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 TNF\u3b1 in patients with HF. Serum gp91phox (NOX2), the catalytic core of NADPH oxidase, and serum TNF\u3b1 were measured in 120 HF patients and in 60 healthy subjects. Compared with healthy subjects, HF patients had higher blood levels of NOX2 and TNF\u3b1 with a progressive increase from NYHA I to NYHA IV classes. NOX2 levels in blood were independently associated with TNF\u3b1 in HF patients. An in vitro study, performed on platelets from a subgroup of HF patients, shows that TNF\u3b1, at concentrations commonly found in HF patients' peripheral circulation, activates platelet NOX2. Thus, TNF\u3b1 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. \ua9 2012 SIMI