Myeloid differentiation factor 2 in the heart: Bench to bedside evidence for potential clinical benefits?

Cardiac inflammation has been involved in many pathological processes in the heart including cardiac hypertrophy, fibrosis, adverse remodeling, and dysfunction. Myeloid differentiation factor 2 (MD2) is a key mediating protein that has been shown to contribute to the inflammatory process. MD2 is required for the activation of TLR4 in the form of dimerization complex. Upon activation of TLR4, the signal can be sent through either myeloid differentiation primary response protein 88 (Myd88) or toll/interleukin-1 receptor (TIR) domain-containing adaptor inducing IFN-β (TRIF) proteins to activate the inflammatory response in cardiac tissue, after which the inflammatory cytokines and genes are produced. In patients with dilated cardiomyopathy, a positive correlation was demonstrated between the serum MD2 levels and mortality rate. Therefore, MD2 inhibition should provide beneficial effects in inflammation related to cardiac diseases such as obesity and heart failure. Multiple inhibitors of TLR4/MD2 interaction reportedly attenuated cardiac dysfunction and remodeling in animals with obesity and heart failure. In this review, we comprehensively summarized the reports from in vitro, in vivo, and clinical studies regarding the role of MD2 and the effects of MD2 inhibitors on cardiac inflammation, dysfunction, fibrosis, and remodeling. The information regarding the beneficial effects of MD2 inhibitors will be used to encourage future clinical use as a novel anti-inflammatory agent.