Opposing roles of Akt and STAT3 in the protection of the maternal heart from peripartum stress

Melanie Ricke-Hoch, Insa Bultmann, Britta Stapel, Gianluigi Condorelli, Ursula Rinas, Karen Sliwa, Michaela Scherr, Denise Hilfiker-Kleiner

Research output: Contribution to journalArticle

Abstract

Background: Peripartum cardiomyopathy (PPCM) is apregnancy-associated cardiomyopathy in previously healthy women. Mice with a cardiomyocyte-restricted deletion of signal transducer and activator of transcription-3 (STAT3, CKO) develop PPCM. PI3K-Akt signallingisthoughtto promote cardiachypertrophy and protection during pregnancy.Weevaluated the role of activated Akt signalling in the maternal heart postpartum Methods and results: CKO mice were bredtomice harbouringanAkt transgene, specifically expressedincardiomyocytes (CAkttg) generating CKO; CAkttg, CAkttg, CKO, and wild-type sibling mice. CAkttg and CKO;CAkttg female mice developed PPCM with systolic dysfunction. Both genotypes displayed cardiac hypertrophy and lower capillary density, showed increased phosphorylation of p66 Src homology 2 domain containing protein and FoxO3A, and reduced expression of manganese superoxide dismutase as well as increased cathepsin D activity and increased miR-146a levels [indicative for generation of the anti-angiogenic 16 kDa prolactin (PRL)]. Cardiac inflammation and fibrosis was accelerated in CKO;CAkttg and associated with high postpartum mortality. The PRL blocker, bromocriptine (BR), prevented heart failure and the decrease in capillary density in CKO;CAkttg and CAkttg mice. BR attenuated high mortality, up-regulation of CCL2, and cardiac inflammation as well as fibrosis in CKO;CAkttg. PRL infusion induced cardiac inflammation in CKO;CAkttg independent of pregnancy. In neonatal rat cardiomyocytes, PRL and interferon γ (IFNγ) induced the expression of CCL2 via activation of Akt. Conclusion: Postpartum Akt activation is detrimental for the peripartum heart as it lowers anti-oxidative defence and in combination with low STAT3 conditions, accelerate cardiac inflammation and fibrosis. PRL and its cleaved 16 kDa form are central for Akt-induced PPCM as indicated by the protection from the disease by PRL blockade.

Original languageEnglish
Pages (from-to)587-596
Number of pages10
JournalCardiovascular Research
Volume101
Issue number4
DOIs
Publication statusPublished - 2014

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Keywords

  • Akt
  • Heart failure
  • Inflammation
  • Peripartum cardiomyopathy
  • Prolactin
  • STAT3

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology
  • Medicine(all)

Cite this

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. Cardiovascular Research, 101(4), 587-596. https://doi.org/10.1093/cvr/cvu010