Inhibition of SENP2-mediated Akt deSUMOylation promotes cardiac regeneration via activating Akt pathway.

Posttranslational modification by SUMO is a key regulator of cell proliferation and can be readily reversed by a family of SUMO-specific proteases (SENPs), making SUMOylation an ideal regulatory mechanism for developing novel therapeutic strategies for promoting a cardiac regenerative response. However, the role of SUMOylation in cardiac regeneration remains unknown. In the present study, we assessed whether targeting Akt SUMOylation can promote cardiac regeneration. Quantitative PCR and western blotting results showed that SENP2 is upregulated during postnatal heart development. SENP2 deficiency promoted P7 and adult cardiomyocyte dedifferentiation and proliferation both in vitro and in vivo. Mice with SENP2 deficiency exhibited improved cardiac function after MI due to cardiomyocyte proliferation and angiogenesis. Mechanistically, the loss of SENP2 upregulated Akt SUMOylation levels and increased Akt kinase activity, leading to a decrease in GSK3β levels and subsequently promoting cardiomyocyte proliferation and angiogenesis. In summary, inhibition of SENP2-mediated Akt deSUMOylation promotes cardiomyocyte differentiation and proliferation by activating the Akt pathway. Our results provide new insights into the role of SUMOylation in cardiac regeneration.