Complexity of TNF-α Signaling in Heart Disease

Heart disease is a leading cause of death with unmet clinical needs for targeted treatment options. Tumor necrosis factor alpha (TNF-alpha) represents a master pro-inflammatory cytokine that plays an important role in many immunopathogenic processes. Anti-TNF-alpha therapy is widely used in treating autoimmune inflammatory disorders, but in case of patients with heart disease, this treatment was unsuccessful or even harmful. The underlying reasons remain elusive until today. This review summarizes the effects of anti-TNF-alpha treatment in patients with and without heart disease and describes the involvement of TNF-alpha signaling in a number of animal models of cardiovascular diseases. We specifically focused on the role of TNF-alpha in specific cardiovascular conditions and in defined cardiac cell types. Although some mechanisms, mainly in disease development, are quite well known, a comprehensive understanding of TNF-alpha signaling in the failing heart is still incomplete. Published data identify pathogenic and cardioprotective mechanisms of TNF-alpha in the affected heart and highlight the differential role of two TNF-alpha receptors pointing to the complexity of the TNF-alpha signaling. In the light of these findings, it seems that targeting the TNF-alpha pathway in heart disease may show therapeutic benefits, but this approach must be more specific and selectively block pathogenic mechanisms. To this aim, more research is needed to better understand the molecular mechanisms of TNF-alpha signaling in the failing heart.