BackgroundPeripartum cardiomyopathy (PPCM) is a pregnancy-associated cardiomyopathy in previously healthy women. Mice with a cardiomyocyte-restricted deletion of STAT3 (CKO) develop PPCM. PI3K-Akt signaling is thought to promote cardiac hypertrophy and protection during pregnancy. We evaluated the role of activated Akt-signaling in the maternal heart postpartum. METHODS AND RESULTS: CKO mice were bred to mice harboring an Akt transgene, specifically expressed in cardiomyocytes (CAkttg) generating CKO;CAkttg, CAkttg, CKO and wildtype 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 p66SHC and FoxO3A and reduced expression of MnSOD as well as increased Cathepsin D activity and increased miR-146a levels (indicative for generation of the anti-angiogenic 16 kDa prolactin). Cardiac inflammation and fibrosis was accelerated in CKO;CAkttg and associated with high postpartum mortality. The prolactin blocker, Bromocriptine, prevented heart failure and the decrease in capillary density in CKO;CAkttg and in CAkttg mice. Bromocriptine attenuated high mortality, up-regulation of CCL2 and cardiac inflammation as well as fibrosis in CKO;CAkttg. Prolactin infusion induced cardiac inflammation in CKO;CAkttg independent of pregnancy. In neonatal rat cardiomyocytes, prolactin 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 defense and in combination with low STAT3 conditions, accelerate cardiac inflammation and fibrosis. Prolactin and its cleaved 16 kDa form are central for Akt-induced PPCM as indicated by the protection from the disease by prolactin blockade.
|Titolo:||Opposing roles of Akt and STAT3 in protection of the maternal heart from peripartum stress|
|Parole Chiave:||Heart Failure; Cell signaling ; Apoptosis|
|Settore Scientifico Disciplinare:||Settore MED/11 - Malattie dell'Apparato Cardiovascolare|
|Data di pubblicazione:||2014|
|Digital Object Identifier (DOI):||10.1093/cvr/cvu010|
|Appare nelle tipologie:||01 - Articolo su periodico|