Skip to main content

Advertisement

SpringerLink
Log in

Pregnancy-induced physiological hypertrophic preconditioning attenuates pathological myocardial hypertrophy by activation of FoxO3a

  • Original Article
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH (2016) ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European society of cardiology (ESC) developed with the special contribution of the heart failure association (HFA) of the ESC. Eur Heart J 37(27):2129–2200. https://doi.org/10.1093/eurheartj/ehw128

    Article  PubMed  Google Scholar 

  2. Wei X, Wu B, Zhao J, Zeng Z, Xuan W, Cao S, Huang X, Asakura M, Xu D, Bin J, Kitakaze M, Liao Y (2015) Myocardial hypertrophic preconditioning attenuates cardiomyocyte hypertrophy and slows progression to heart failure through upregulation of S100A8/A9. Circulation 131(17):1506–1517. https://doi.org/10.1161/CIRCULATIONAHA.114.013789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ma LL, Ding ZW, Yin PP, Wu J, Hu K, Sun AJ, Zou YZ, Ge JB (2021) Hypertrophic preconditioning cardioprotection after myocardial ischaemia/reperfusion injury involves ALDH2-dependent metabolism modulation. Redox Biol 43:101960. https://doi.org/10.1016/j.redox.2021.101960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ma LL, Kong FJ, Dong Z, Xin KY, Wang XX, Sun AJ, Zou YZ, Ge JB (2021) Hypertrophic preconditioning attenuates myocardial Ischaemia-reperfusion Injury by modulating SIRT3-SOD2-mROS-dependent autophagy. Cell Prolif 54(7):e13051. https://doi.org/10.1111/cpr.13051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ma LL, Kong FJ, Ma YJ, Guo JJ, Wang SJ, Dong Z, Sun AJ, Zou YZ, Ge JB (2021) Hypertrophic preconditioning attenuates post-myocardial infarction injury through deacetylation of isocitrate dehydrogenase 2. Acta Pharmacol Sin 42(12):2004–2015. https://doi.org/10.1038/s41401-021-00699-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wu J, Lu J, Huang J, You J, Ding Z, Ma L, Dai F, Xu R, Li X, Yin P, Zhao G, Wang S, Yuan J, Yang X, Ge J, Zou Y (2020) Variations in energy metabolism precede alterations in cardiac structure and function in hypertrophic preconditioning. Front Cardiovasc Med. https://doi.org/10.3389/fcvm.2020.602100

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lin H, Zhu Y, Zheng C, Hu D, Ma S, Chen L, Wang Q, Chen Z, Xie J, Yan Y, Huang X, Liao W, Kitakaze M, Bin J, Liao Y (2021) Antihypertrophic memory after regression of exercise-induced physiological myocardial hypertrophy is mediated by the long noncoding RNA Mhrt779. Circulation 143(23):2277–2292. https://doi.org/10.1161/CIRCULATIONAHA.120.047000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhu Y, Zheng C, Zhang R, Yan J, Li M, Ma S, Chen K, Chen L, Liu J, Xiu J, Liao W, Bin J, Huang J, Lin H, Liao Y (2022) Circ-Ddx60 contributes to the antihypertrophic memory of exercise hypertrophic preconditioning. J Adv Res. https://doi.org/10.1016/j.jare.2022.06.005

    Article  PubMed  PubMed Central  Google Scholar 

  9. Sanghavi M, Rutherford JD (2014) Cardiovascular physiology of pregnancy. Circulation 130(12):1003–1008. https://doi.org/10.1161/CIRCULATIONAHA.114.009029

    Article  PubMed  Google Scholar 

  10. Kara RJ, Bolli P, Karakikes I, Matsunaga I, Tripodi J, Tanweer O, Altman P, Shachter NS, Nakano A, Najfeld V, Chaudhry HW (2012) Fetal cells traffic to injured maternal myocardium and undergo cardiac differentiation. Circ Res 110(1):82–93. https://doi.org/10.1161/CIRCRESAHA.111.249037

    Article  CAS  PubMed  Google Scholar 

  11. Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL, Baughman KL, Kasper EK (2000) Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 342(15):1077–1084. https://doi.org/10.1056/NEJM200004133421502

    Article  CAS  PubMed  Google Scholar 

  12. Haghikia A, Podewski E, Libhaber E, Labidi S, Fischer D, Roentgen P, Tsikas D, Jordan J, Lichtinghagen R, von Kaisenberg CS, Struman I, Bovy N, Sliwa K, Bauersachs J, Hilfiker-Kleiner D (2013) Phenotyping and outcome on contemporary management in a German cohort of patients with peripartum cardiomyopathy. Basic Res Cardiol 108(4):366. https://doi.org/10.1007/s00395-013-0366-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gagnon A (2015) Natural fertility and longevity. Fertil Steril 103(5):1109–1116. https://doi.org/10.1016/j.fertnstert.2015.03.030

    Article  PubMed  Google Scholar 

  14. Hall PS, Nah G, Howard BV, Lewis CE, Allison MA, Sarto GE, Waring ME, Jacobson LT, Manson JE, Klein L, Parikh NI (2017) Reproductive factors and incidence of heart failure hospitalization in the women’s health initiative. J Am Coll Cardiol 69(20):2517–2526. https://doi.org/10.1016/j.jacc.2017.03.557

    Article  PubMed  PubMed Central  Google Scholar 

  15. Ni YG, Berenji K, Wang N, Oh M, Sachan N, Dey A, Cheng J, Lu G, Morris DJ, Castrillon DH, Gerard RD, Rothermel BA, Hill JA (2006) Foxo transcription factors blunt cardiac hypertrophy by inhibiting calcineurin signaling. Circulation 114(11):1159–1168. https://doi.org/10.1161/CIRCULATIONAHA.106.637124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sundaresan NR, Gupta M, Kim G, Rajamohan SB, Isbatan A, Gupta MP (2009) Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J Clin Invest 119(9):2758–2771. https://doi.org/10.1172/JCI39162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ricke-Hoch M, Bultmann I, Stapel B, Condorelli G, Rinas U, Sliwa K, Scherr M, Hilfiker-Kleiner D (2014) Opposing roles of Akt and STAT3 in the protection of the maternal heart from peripartum stress. Cardiovasc Res 101(4):587–596. https://doi.org/10.1093/cvr/cvu010

    Article  CAS  PubMed  Google Scholar 

  18. Papait R, Cattaneo P, Kunderfranco P, Greco C, Carullo P, Guffanti A, Vigano V, Stirparo GG, Latronico MV, Hasenfuss G, Chen J, Condorelli G (2013) Genome-wide analysis of histone marks identifying an epigenetic signature of promoters and enhancers underlying cardiac hypertrophy. Proc Natl Acad Sci U S A 110(50):20164–20169. https://doi.org/10.1073/pnas.1315155110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Li J, Umar S, Iorga A, Youn JY, Wang Y, Regitz-Zagrosek V, Cai H, Eghbali M (2012) Cardiac vulnerability to ischemia/reperfusion injury drastically increases in late pregnancy. Basic Res Cardiol 107(4):271. https://doi.org/10.1007/s00395-012-0271-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mikhail MA, M’Hamdi H, Welsh J, Levicar N, Marley SB, Nicholls JP, Habib NA, Louis LS, Fisk NM, Gordon MY (2008) High frequency of fetal cells within a primitive stem cell population in maternal blood. Hum Reprod 23(4):928–933. https://doi.org/10.1093/humrep/dem417

    Article  PubMed  Google Scholar 

  21. Morris EA, Hale SA, Badger GJ, Magness RR, Bernstein IM (2015) Pregnancy induces persistent changes in vascular compliance in primiparous women. Am J Obstet Gynecol. https://doi.org/10.1016/j.ajog.2015.01.005

    Article  PubMed  PubMed Central  Google Scholar 

  22. Laufer N (2015) Introduction: fertility and longevity. Fertil Steril 103(5):1107–1108. https://doi.org/10.1016/j.fertnstert.2015.03.012

    Article  PubMed  Google Scholar 

  23. Greer EL, Maures TJ, Hauswirth AG, Green EM, Leeman DS, Maro GS, Han S, Banko MR, Gozani O, Brunet A (2010) Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature. https://doi.org/10.1038/nature09195

    Article  PubMed  PubMed Central  Google Scholar 

  24. Jaspers L, Kavousi M, Erler NS, Hofman A, Laven JS, Franco OH (2017) Fertile lifespan characteristics and all-cause and cause-specific mortality among postmenopausal women: the Rotterdam Study. Fertil Steril. https://doi.org/10.1016/j.fertnstert.2016.11.006

    Article  PubMed  Google Scholar 

  25. Petrov G, Regitz-Zagrosek V, Lehmkuhl E, Krabatsch T, Dunkel A, Dandel M, Dworatzek E, Mahmoodzadeh S, Schubert C, Becher E, Hampl H, Hetzer R (2010) Regression of myocardial hypertrophy after aortic valve replacement: faster in women? Circulation 122(11 Suppl):S23–S28. https://doi.org/10.1161/CIRCULATIONAHA.109.927764

    Article  PubMed  Google Scholar 

  26. Cao DJ, Jiang N, Blagg A, Johnstone JL, Gondalia R, Oh M, Luo X, Yang KC, Shelton JM, Rothermel BA, Gillette TG, Dorn GW, Hill JA (2013) Mechanical unloading activates FoxO3 to trigger Bnip3-dependent cardiomyocyte atrophy. J Am Heart Assoc 2(2):e000016. https://doi.org/10.1161/JAHA.113.000016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Choi S, Jeong HJ, Kim H, Choi D, Cho SC, Seong JK, Koo SH, Kang JS (2019) Skeletal muscle-specific Prmt1 deletion causes muscle atrophy via deregulation of the PRMT6-FOXO3 axis. Autophagy 15(6):1069–1081. https://doi.org/10.1080/15548627.2019.1569931

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Trivedi CM, Luo Y, Yin Z, Zhang M, Zhu W, Wang T, Floss T, Goettlicher M, Noppinger PR, Wurst W, Ferrari VA, Abrams CS, Gruber PJ, Epstein JA (2007) Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activity. Nat Med 13(3):324–331. https://doi.org/10.1038/nm1552

    Article  PubMed  Google Scholar 

  29. Ahmad F, Lal H, Zhou J, Vagnozzi RJ, Yu JE, Shang X, Woodgett JR, Gao E, Force T (2014) Cardiomyocyte-specific deletion of Gsk3alpha mitigates post-myocardial infarction remodeling, contractile dysfunction, and heart failure. J Am Coll Cardiol 64(7):696–706. https://doi.org/10.1016/j.jacc.2014.04.068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cho J, Zhai P, Maejima Y, Sadoshima J (2011) Myocardial injection with GSK-3beta-overexpressing bone marrow-derived mesenchymal stem cells attenuates cardiac dysfunction after myocardial infarction. Circ Res 108(4):478–489. https://doi.org/10.1161/CIRCRESAHA.110.229658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. van de Schans VA, van den Borne SW, Strzelecka AE, Janssen BJ, van der Velden JL, Langen RC, Wynshaw-Boris A, Smits JF, Blankesteijn WM (2007) Interruption of Wnt signaling attenuates the onset of pressure overload-induced cardiac hypertrophy. Hypertension 49(3):473–480. https://doi.org/10.1161/01.HYP.0000255946.55091.24

    Article  CAS  PubMed  Google Scholar 

  32. Lin H, Li Y, Zhu H, Wang Q, Chen Z, Chen L, Zhu Y, Zheng C, Wang Y, Liao W, Bin J, Kitakaze M, Liao Y (2019) Lansoprazole alleviates pressure overload-induced cardiac hypertrophy and heart failure in mice by blocking the activation of beta-catenin. Cardiovasc Res. https://doi.org/10.1093/cvr/cvz016

    Article  PubMed  Google Scholar 

  33. Hao H, Li X, Li Q, Lin H, Chen Z, Xie J, Xuan W, Liao W, Bin J, Huang X, Kitakaze M, Liao Y (2016) FGF23 promotes myocardial fibrosis in mice through activation of beta-catenin. Oncotarget 7(40):64649–64664. https://doi.org/10.18632/oncotarget.11623

    Article  PubMed  PubMed Central  Google Scholar 

  34. Chen Z, Xie J, Hao H, Lin H, Wang L, Zhang Y, Chen L, Cao S, Huang X, Liao W, Bin J, Liao Y (2017) Ablation of periostin inhibits post-infarction myocardial regeneration in neonatal mice mediated by the phosphatidylinositol 3 kinase/glycogen synthase kinase 3beta/cyclin D1 signalling pathway. Cardiovasc Res 113(6):620–632. https://doi.org/10.1093/cvr/cvx001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Li Y, Wang Z, Kong D, Li R, Sarkar SH, Sarkar FH (2008) Regulation of Akt/FOXO3a/GSK-3beta/AR signaling network by isoflavone in prostate cancer cells. J Biol Chem 283(41):27707–27716. https://doi.org/10.1074/jbc.M802759200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Luo M, Wu C, Guo E, Peng S, Zhang L, Sun W, Liu D, Hu G, Hu G (2019) FOXO3a knockdown promotes radioresistance in nasopharyngeal carcinoma by inducing epithelial-mesenchymal transition and the Wnt/beta-catenin signaling pathway. Cancer Lett 455:26–35. https://doi.org/10.1016/j.canlet.2019.04.019

    Article  CAS  PubMed  Google Scholar 

  37. Zhao Y, Wang C, Hong X, Miao J, Liao Y, Hou FF, Zhou L, Liu Y (2019) Wnt/beta-catenin signaling mediates both heart and kidney injury in type 2 cardiorenal syndrome. Kidney Int 95(4):815–829. https://doi.org/10.1016/j.kint.2018.11.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hao H, Ma S, Zheng C, Wang Q, Lin H, Chen Z, Xie J, Chen L, Chen K, Wang Y, Huang X, Cao S, Liao W, Bin J, Liao Y (2021) Excessive fibroblast growth factor 23 promotes renal fibrosis in mice with type 2 cardiorenal syndrome. Aging (Albany NY) 13(2):2982–3009. https://doi.org/10.18632/aging.202448

    Article  CAS  PubMed  Google Scholar 

  39. Shingo T, Gregg C, Enwere E, Fujikawa H, Hassam R, Geary C, Cross JC, Weiss S (2003) Pregnancy-stimulated neurogenesis in the adult female forebrain mediated by prolactin. Science 299(5603):117–120. https://doi.org/10.1126/science.1076647

    Article  CAS  PubMed  Google Scholar 

Download references

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).

Funding

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).

Author information

Author notes

  1. Jiahe Xie and Cankun Zheng have contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Lab of Cardiac Function and Microcirculation, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou, 510515, China

    Jiahe Xie, Cankun Zheng, Mengjia Shen, Mingjue Li, Mingyuan He, Lu Chen, Siyuan Ma, Yingqi Zhu, Hairuo Lin, Jiancheng Xiu, Jianping Bin & Yulin Liao

  2. Department of Cardiology, First Affiliated Hospital, Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Jiangxi Branch Center of National Geriatric Disease Clinical Medical Research Center, Gannan Medical University, Ganzhou, 341000, China

    Jiahe Xie & Weiling Lu

  3. Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China

    Wangjun Liao

  4. National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China

    Jianping Bin & Yulin Liao

Authors
  1. Jiahe Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cankun Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mengjia Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Weiling Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mingjue Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mingyuan He
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Siyuan Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yingqi Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hairuo Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jiancheng Xiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Wangjun Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jianping Bin
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yulin Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Yulin Liao.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures were performed in accordance with our Institutional Guidelines for Animal Research, and this investigation conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (National Institutes of Health Publication, 8th Edition, 2011). This study was approved by ethics review board of Southern Medical University.

Consent for publication

This study does not contain any individual person’s data. All authors agree for publication.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 1713 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00018-023-04909-2

Keywords

Search

Navigation