TNFalpha is crucially involved in the pathogenesis and progression of atherosclerosis, myocardial ischemia/reperfusion injury and heart failure. The formation and release of TNFalpha and its downstream signal transduction cascade following activation of its two receptor subtypes is characterized, with special emphasis on the cardiovascular system. In the vasculature, TNFalpha alters endothelial and vascular smooth muscle cell function as well as endothelial cell-blood cell interaction; the importance of such alterations for vascular dysfunction, the initiation and progression of atherosclerosis are discussed. In the myocardium, TNFalpha contributes to reversible and irreversible ischemia/reperfusion injury, post-myocardial infarction remodeling and heart failure development. Simultaneously, TNFalpha also contributes to cardioprotection by ischemic conditioning. Emphasis is placed on such ambivalent (detrimental vs. beneficial) role of TNFalpha, which appears to be dose- and time-dependent and in part related to the activation of the specific receptor subtype. Given the ambivalent role of TNFalpha and its receptors, it is not surprising that clinical trials using compounds that antagonize TNFalpha revealed ambiguous and largely disappointing results in cardiovascular disease, notably in heart failure. Future perspectives to antagonize and/or potentially recruit TNFalpha in the cardiovascular system are critically discussed.
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