Abstract
Previous studies show a woman’s pregnancy is correlated with post-reproductive longevity, and nulliparity is associated with higher risk of incident heart failure, suggesting pregnancy likely exerts a cardioprotection. We previously reported a cardioprotective phenomenon termed myocardial hypertrophic preconditioning, but it is unknown whether pregnancy-induced physiological hypertrophic preconditioning (PHP) can also protect the heart against subsequent pathological hypertrophic stress. We aimed to clarify the phenomenon of PHP and its mechanisms. The pluripara mice whose pregnancy-induced physiological hypertrophy regressed and the nulliparous mice underwent angiotensin II (Ang II) infusion or transverse aortic constriction (TAC). Echocardiography, invasive left ventricular hemodynamic measurement and histological analysis were used to evaluate cardiac remodeling and function. Silencing or overexpression of Foxo3 by adeno-associated virus was used to investigate the role of FoxO3a involved in the antihypertrophic effect. 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 PHP. 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 Foxo3 attenuated or enhanced the anti-hypertrophic effect of PHP in mice with pathological stimulation. Our findings demonstrate that PHP confers resistance to subsequent hypertrophic stress and slows progression to heart failure through activation of FoxO3a/GSK3β pathway.
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The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
YL acknowledges grants from the National Natural Science Foundation of China (81770271 to YL), the Joint Funds of the National Natural Science Foundation of China (U1908205 to YL), the National Natural Science Foundation of China (82170278 to YL), and the Municipal Project of Research and Utilization of Healthcare Key Technology in Guangzhou (202206010199 to YL). JX was supported by the Scientific Research Project of Gannan Medical University (ZD201825 to JX).
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This work was supported by grants from the National Natural Science Foundation of China (81770271 to YL), the Joint Funds of the National Natural Science Foundation of China (U1908205 to YL), the National Natural Science Foundation of China (82170278 to YL), and the Municipal Project of Research and Utilization of Healthcare Key Technology in Guangzhou (202206010199 to YL), the Scientific Research Project of Gannan Medical University (ZD201825 to JX).
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JX and CZ performed experimental design and executed most of the experiments, data analyses, and wrote the manuscript. MS, WL, and HL contributed to the technical, and material support. ML, MH, LC, SM, YZ, HL, JX, WL, and JB contributed to the data interpretation and discussion. LY contributed to the concept design, data interpretation, writing and revising the manuscript. All authors reviewed the results and approved the final version of the manuscript.
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Xie, J., Zheng, C., Shen, M. et al. Pregnancy-induced physiological hypertrophic preconditioning attenuates pathological myocardial hypertrophy by activation of FoxO3a. Cell. Mol. Life Sci. 80, 267 (2023). https://doi.org/10.1007/s00018-023-04909-2
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DOI: https://doi.org/10.1007/s00018-023-04909-2