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.
- Heart failure
- Peripartum cardiomyopathy
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)