Figure 1.

The pleotropic actions of STAT3 in the heart and their interplay. STAT3 has both canonical and non-canonical actions that impact on the viability of the myocardium. Canonical STAT3-induced gene expression is associated with the upregulation of protective anti-oxidant and anti-apoptotic proteins, as well as maintaining the heath of the endothelium (e.g., by upregulating VEGF and SOD2). STAT3 induces its own expression leading potentially to the accumulation of unphosphorylated STAT3 (U-STAT3) in the nucleus, which has been associated with hypertrophy and inflammation. U-STAT3 may contribute to chromatin stability and gene suppression. STAT3 also directly suppresses/represses genes possibly by association with DNMT1 or HDACs. Loss of STAT3-mediated suppression of miR-199a-5p has been linked to endothelial dysfunction (center arrow). Gene repression may be important for mitochondrial biogenesis. STAT3 has direct mitochondrial actions that are poorly understood, but involve maintaining complex I/II activity and preventing mPTP opening. By sequestering STAT3 (perhaps involving redox modifications), mitochondria may reduce the nuclear transcriptional actions of STAT3. Canonical STAT3 signaling is likely important for mitochondrial health as well.