β-adrenergic receptor inhibits heart regeneration by downregulating Yap m6A modification.

Newborn mammals transiently maintain the heart regenerative capacity. β-adrenergic receptor (β-AR) is the most critical receptor in regulating cardiomyocyte behavior. However, the role and mechanism of β-AR, especially the subtypes of β-AR, in heart regeneration remain unclear. Here, we reveal that β-AR inhibits heart regeneration by downregulating Yap m6A modification. The β-AR expression is associated with heart regenerative capacity. After apical resection, β-AR (including β(1)-AR and β(2)-AR) inhibits heart regeneration. β(2)-AR exerts a more potent inhibitory effect compared with β(1)-AR. Mechanistically, both β(1)-AR and β(2)-AR downregulate Yap m6A modification and then YAP expression differentially by reducing METTL14 and IGF2BP1, respectively. Elevation of Yap m6A modification with adenoviruses encoding METTL14 and IGF2BP1 rescues YAP expression and cardiomyocyte proliferation inhibited by β(1)-AR and β(2)-AR, respectively. These findings indicate that both β(1)-AR and β(2)-AR inhibit heart regeneration in a m6A-dependent manner and reveal subtype-specific mechanism. These results will provide a new intervention strategy for heart regeneration.