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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Peripartum Period
Prolactin
Cardiomyopathies
Mothers
Postpartum Period
Inflammation
Fibrosis
Bromocriptine
Cardiac Myocytes
STAT3 Transcription Factor
Pregnancy
Cathepsin D
src Homology Domains
Mortality
Cardiomegaly
Transgenes
Phosphatidylinositol 3-Kinases
Interferons
Superoxide Dismutase
Siblings

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., ... 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

Opposing roles of Akt and STAT3 in the protection of the maternal heart from peripartum stress. / Ricke-Hoch, Melanie; Bultmann, Insa; Stapel, Britta; Condorelli, Gianluigi; Rinas, Ursula; Sliwa, Karen; Scherr, Michaela; Hilfiker-Kleiner, Denise.

In: Cardiovascular Research, Vol. 101, No. 4, 2014, p. 587-596.

Research output: Contribution to journalArticle

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, vol. 101, no. 4, pp. 587-596. https://doi.org/10.1093/cvr/cvu010
Ricke-Hoch, Melanie ; Bultmann, Insa ; Stapel, Britta ; Condorelli, Gianluigi ; Rinas, Ursula ; Sliwa, Karen ; Scherr, Michaela ; Hilfiker-Kleiner, Denise. / Opposing roles of Akt and STAT3 in the protection of the maternal heart from peripartum stress. In: Cardiovascular Research. 2014 ; Vol. 101, No. 4. pp. 587-596.
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AU - Condorelli, Gianluigi

AU - Rinas, Ursula

AU - Sliwa, Karen

AU - Scherr, Michaela

AU - Hilfiker-Kleiner, Denise

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N2 - 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.

AB - 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.

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