Pregnancy-induced Physiological Hypertrophic Preconditioning Attenuates Pathological Myocardial Hypertrophy by Mnemonic Activation of FoxO3a/GSK3β Pathway

Abstract

Previous studies show a woman’s age at final pregnancy is correlated with post-reproductive longevity and nulliparity is associated with higher risk of incident heart failure, and we previously reported a cardioprotective phenomenon termed myocardial hypertrophic preconditioning, but it is unknown whether pregnancy-induced physiological hypertrophic preconditioning can also protect the heart against subsequent pathological hypertrophic stress. Here, we found that compared with nulliparous mice, pathological cardiac hypertrophy induced by Ang Ⅱ infusion or TAC was significantly attenuated and heart failure induced by TAC was markedly improved in mice with pregnant preconditioning. Activation of FoxO3a was significantly enhanced in the hearts of postpartum mice. FoxO3a inhibited myocardial hypertrophy by suppressing signaling pathway of phosphorylated glycogen synthase kinase-3β (p-GSK3β)/β-catenin/Cyclin D1. Silencing or overexpression of FoxO3a attenuated or enhanced the anti-hypertrophic effect of pregnant preconditioning in mice with pathological stimulation. Our findings demonstrate that pregnancy-induced myocardial hypertrophic preconditioning confers resistance to subsequent hypertrophic stress and slows progression to heart failure through activation of FoxO3a/GSK3β pathway.