Extended Data Figure 10.

Mechanism model of Pitx2, Nrf2, and Yap responding to oxidative stress. When oxidative stress is low, Nrf2 is sequestered in cytoplasm by its degradation complex (Cul3, Keap1), and Pitx2 stays either in cytoplasm or at low expression level. When redox balance is disturbed by ROS, Nrf2 breaks away from degradation complex, and enter nuclei to up-regulate Pitx2, Nrf2 also binds cytoplasmic Pitx2 and shuttle it to nuclei, where Pitx2 and Yap co-regulate their common targets including critical antioxidant genes. In wild type adult mouse heart, active Yap is maintained at a low level, even after ischemic injury, thus not able to repair myocardium efficiently. When Pitx2 is over-expressed in cardiomyocytes, sufficient amount of Pitx2 will cooperate with low level of resident active Yap to induce the expression of beneficial antioxidant scavengers in a synergetic pattern, rendering protection to injured myocardium. Red arrow, supported by in vitro evidence; Blue arrows, supported by in vivo evidence.