TNF-a was originally identified as a macrophage product implicated in the metabolic disturbances of chronic inflammation and malignancy. Later on, its biological actions were shown to further extend to anorexia, weight loss, and insulin resistance (7). Elevated adipose tissue expression of TNF-a mRNA has been reported in different rodent models of obesity as well as in clinical studies involving obese patients (23). TNF-a mRNA expression is positively correlated with body adiposity as well as with hyperinsulinemia, showing positive associations with fasting insulin and triglyceride concentrations. TNF-a inhibits the expression of the transcription factor CCAAT/ enhancer binding protein-a (CEBPa) and the nuclear receptor peroxisome proliferator-activated receptor (PPAR)y2 (8,12,14). Furthermore, TNF-a stimulates the nuclear factor- kB transcription factor (NFkB), which orchestrates a series of inflammatory events, including expression of adhesion molecules on the surface of both endothelial cells and VSMC (8,11,24). Regarding the impact on the cardiac sphere, the deleterous effects of TNF-a on left ventricular dysfunction reportedly take place in the short term through stimulation of the neutral sphingomyelinase pathway, whereas the more delayed response is mediated by a NO-induced blunting of the ^-adrenergic signaling, resulting in a negative inotropism (17). Further inflammatory cytokines, such as IL-1, IL-18, and IL-6, are also known to be released and activated in heart failure.
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