Deciphering STAT3 signaling in the heart: plasticity and vascular inflammation

Abstract

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that plays a critical role in heart development and protection. New developments in understanding its molecular chemistry have revealed the importance of STAT3 in controlling mitochondrial respiration, independent of its function as a transcription factor, and in modulating inflammatory signaling through interactions with other transcription factors and cofactors. The purpose of this article is 2-fold. First, the authors summarize some recent insights into the function of STAT3. Second, the authors seek to illustrate the complexity of targeting a particular cellular protein for therapeutic purposes and the need to consider context when attempting to decipher the role of a particular signaling pathway in the heart. In this case, inflammation, aging, hypertrophy, and heart failure provide new environments that certainly impact on the functioning of STAT3 and on the gene profile linked to its activation.

Figure 1

Domain structures of STAT3 showing the key sites for phosphorylation (Y705 and S727) and acetylation (K49, K87, and K685). SH2, src homology 2; TAD, transcription activation domain.

Figure 2

Hypothetical impact of increasing inflammatory stress on transcriptional response of endothelial cells to IL-6 type cytokine stimulation. The IL-6 cytokines activate STAT3 by increasing phosphorylation of Y705 and to a lesser extent S727: ➀No stress situation with minimal S727 phosphorylation; ➁STAT3 - NF-κB p65 association with mild inflammation; NF-κB would be activated by oxidative stress or some cytokine like TNFα; ➂Notable inflammation with markedly increased S727 phosphorylation and recruitment of the transcription factor Sp1. S727 phosphorylation might be increased by stress kinases or inhibition of the phosphatase PP2A due to oxidative stress. PP2A inhibition would affect Sp1 activity as well.