TNFα in myocardial ischemia/reperfusion, remodeling and heart failure.
TNFα is crucially involved in the pathogenesis and progression of myocardial ischemia/reperfusion injury and heart failure. The formation and release of TNFα and its downstream signal transduction cascade following activation of its two receptor subtypes are characterized. Myocardial TNFα and TNF receptor activation have an ambivalent role in myocardial ischemia/reperfusion injury and protection from it. Excessive TNFα expression and subsequent cardiomyocyte TNF receptor type 1 stimulation induce contractile dysfunction, hypertrophy, fibrosis and cell death, while a lower TNFα concentration and subsequent cardiomyocyte TNF receptor type 2 stimulation are protective. Apart from its concentration and receptor subtype, the myocardial action of TNFα depends on the duration of its exposure and its localization. While detrimental during sustained ischemia, TNFα contributes to ischemic preconditioning protection, no matter whether it is the first, second or third window of protection, and both TNF receptors are involved in the protective signal transduction cascade. Finally, the available clinical attempts to antagonize TNFα in cardiovascular disease, notably heart failure, are critically discussed.
Kleinbongard
Petra
P
Institut für Pathophysiologie, Universitätsklinikum Essen, Hufelandstrasse 55, 45122, Essen, Germany.
Schulz
Rainer
R
Heusch
Gerd
G
D015415:Biomarkers; D018450:Disease Progression; D005355:Fibrosis / Q000473:pathology*; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000473:pathology; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000473:pathology; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000473:pathology*; D011110:Polymorphism, Genetic; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*
D015415:Biomarkers; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha