Details
| Original language | English |
|---|---|
| Pages (from-to) | 587-596 |
| Number of pages | 10 |
| Journal | Cardiovascular research |
| Volume | 101 |
| Issue number | 4 |
| Early online date | 20 Jan 2014 |
| Publication status | Published - 15 Mar 2014 |
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.
Keywords
- Akt, Heart failure, Inflammation, Peripartum cardiomyopathy, Prolactin, STAT3
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Physiology
- Medicine(all)
- Cardiology and Cardiovascular Medicine
- Medicine(all)
- Physiology (medical)
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In: Cardiovascular research, Vol. 101, No. 4, 15.03.2014, p. 587-596.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Opposing roles of Akt and STAT3 in the protection of the maternal heart from peripartum stress
AU - Ricke-Hoch, Melanie
AU - Bultmann, Insa
AU - Stapel, Britta
AU - Condorelli, Gianluigi
AU - Rinas, Ursula
AU - Sliwa, Karen
AU - Scherr, Michaela
AU - Hilfiker-Kleiner, Denise
PY - 2014/3/15
Y1 - 2014/3/15
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.
KW - Akt
KW - Heart failure
KW - Inflammation
KW - Peripartum cardiomyopathy
KW - Prolactin
KW - STAT3
UR - http://www.scopus.com/inward/record.url?scp=84901485282&partnerID=8YFLogxK
U2 - 10.1093/cvr/cvu010
DO - 10.1093/cvr/cvu010
M3 - Article
C2 - 24448315
AN - SCOPUS:84901485282
VL - 101
SP - 587
EP - 596
JO - Cardiovascular research
JF - Cardiovascular research
SN - 0008-6363
IS - 4
ER -