Tumor necrosis factor in the heart.
The heart is a tumor necrosis factor (TNF)-producing organ. Both myocardial macrophages and cardiac myocytes themselves synthesize TNF. Accumulating evidence indicates that myocardial TNF is an autocrine contributor to myocardial dysfunction and cardiomyocyte death in ischemia-reperfusion injury, sepsis, chronic heart failure, viral myocarditis, and cardiac allograft rejection. Indeed, locally (vs. systemically) produced TNF contributes to postischemic myocardial dysfunction via direct depression of contractility and induction of myocyte apoptosis. Lipopolysaccharide or ischemia-reperfusion activates myocardial P38 mitogen-activated protein (MAP) kinase and nuclear factor kappa B, which lead to TNF production. TNF depresses myocardial function by nitric oxide (NO)-dependent and NO-independent (sphingosine dependent) mechanisms. TNF activation of TNF receptor 1 or Fas may induce cardiac myocyte apoptosis. MAP kinases and TNF transcription factors are feasible targets for anti-TNF (i.e., cardioprotective) strategies. Endogenous anti-inflammatory ligands, which trigger the gp130 signaling cascade, heat shock proteins, and TNF-binding proteins, also control TNF production and activity. Thus modulation of TNF in cardiovascular disease represents a realistic goal for clinical medicine.
Meldrum
D R
DR
Department of Surgery, University of Colorado Health Sciences Center, Denver 80262, USA.
D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D002118:Calcium / Q000502:physiology; D006321:Heart / Q000502:physiology*; D006360:Heat-Shock Proteins; D006801:Humans; D019157:Ischemic Preconditioning, Myocardial; D008264:Macrophages / Q000502:physiology; D009200:Myocardial Contraction; D015428:Myocardial Reperfusion Injury / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D000975:Antioxidants; D006360:Heat-Shock Proteins; D014409:Tumor Necrosis Factor-alpha; D000241:Adenosine; D002118:Calcium; D009638:Norepinephrine