Enhanced TNFα and oxidative stress in patients with heart failure: effect of TNFα on platelet O2 - production

Abstract

Experimental studies have suggested that TNF alpha, a pro-inflammatory cytokine, may contribute to the deterioration of cardiovascular function through various mechanisms, including the generation of reactive oxygen species. It has not yet been demonstrated whether TNF alpha has prooxidant activity in patients with heart failure, and what the mechanism eventually resulting in this effect are. We analyzed 42 patients (38 men and 4 women, aged 26 to 74 years) with heart failure, secondary to idiopathic dilated cardiomyopathy (n=21), coronary artery disease (n=15), and valve disease (n=6), and 20 controls (18 men and 2 women, aged 49 to 67 years). Ten patients were in class I, 9 in class II, 15 in class III and 8 in class IV according to NYHA Classification. Blood samples were obtained from each patient to evaluate basal and collagen-induced platelet O(2)(-) production, and plasma TNF alpha. In vivo results showed increased platelet O(2)(-) production and plasma TNF alpha levels in NYHA class III-IV compared with that in controls or in NYHA I-II (p<0,001); platelet O(2)(-) production correlated significantly (R=0,6; p<0,01) with TNF alpha plasma levels. In vitro studies showed TNF alpha dose-dependently (5-40 pg/ml) induced platelet O(2)(-) production, and that this effect was significantly inhibited by its specific inhibitor, WP9QY (1 microM); aspirin (100 microM), AACOCF(3), a specific PLA(2) inhibitor (14 microM), and DPI, an inhibitor of NADPH oxidase, significantly inhibited TNF alpha-mediated platelet O(2)(-) production. This study suggests that in patients with heart failure, enhanced platelet O(2)(-) production is mediated by TNF alpha via activation of arachidonic acid and NADPH oxidase pathways.

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

“…Experimental studies have suggested that TNFa contributes to the generation of ROS [6,23] with a mechanism that could involve the activation of NADPH oxidase [6,7]; however, direct evidence in support of this hypothesis is still lacking. Herein we provide the first evidence that TNFa elicits the activation of NADPH oxidase.…”

“…However, the underlying mechanisms have not been fully elucidated. TNFa-induced oxidative stress may have a role as oxidative stress is also implicated in HF deterioration [6,7]. So far, however, the mechanism linking TNFa with oxidative stress is undefined.…”

“…More recently, TNFa-induced ventricular remodeling has been associated with enhanced NADPH oxidase-mediated reactive oxygen species (ROS) production in a murine model [8]. According to this, TNFa may promote platelet oxidative stress via activation of NADPH oxidase, but direct evidence in support of this hypothesis is still lacking in humans [6,7]. Platelets possess all the subunits of NADPH oxidase [9], which is activated and released in the medium upon stimulation with agonists [10].…”

Hesperidin Produces Cardioprotective Activity via PPAR-γ Pathway in Ischemic Heart Disease Model in Diabetic Rats

“…Treatments available for myocardial infarction (MI) like ischemic injury targets restoration of blood supply to ischemic tissue and prevent the damage inflicted at the time of injury. While at one hand, imbalance between myocardial blood supply and demand resulting in development of ischemia and induction of necrosis in myocardium results in acute MI [3], oxidative stress produced by generation of free radicals or reactive oxygen species also plays a key role in MI development [4], [5]. Therefore, suppressing free radical generation and/or augmentation of endogenous antioxidant enzymes is reported to limit the infarct size and attenuate myocardial dysfunction [6].…”

Oral treatment with Euterpe oleracea Mart. (açaí) extract improves cardiac dysfunction and exercise intolerance in rats subjected to myocardial infarction

“…Increasing numbers of ROS-like hydroxyl radicals and superoxide anions during heart ischemia lead to destruction of the cell membrane, development of lipid peroxides, and damage to the antioxidative defense system [2,3]. Experimental and clinical studies have shown that the infarct size of myocardial necrosis may be limited by the development of endogenous antioxidant enzymes and the suppression of free radical generation [4].…”