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

Cardiovasc Res. 2014 Mar 15;101(4):587-96. doi: 10.1093/cvr/cvu010. Epub 2014 Jan 20.

Abstract

Background: Peripartum cardiomyopathy (PPCM) is a pregnancy-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 signalling is thought to promote cardiac hypertrophy and protection during pregnancy. We evaluated the role of activated Akt signalling in the maternal heart postpartum.

Methods and results: CKO mice were bred to mice harbouring an Akt transgene, specifically expressed in cardiomyocytes (CAkt(tg)) generating CKO; CAkt(tg), CAkt(tg), CKO, and wild-type sibling mice. CAkt(tg) and CKO;CAkt(tg) 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;CAkt(tg) and associated with high postpartum mortality. The PRL blocker, bromocriptine (BR), prevented heart failure and the decrease in capillary density in CKO;CAkt(tg) and CAkt(tg) mice. BR attenuated high mortality, up-regulation of CCL2, and cardiac inflammation as well as fibrosis in CKO;CAkt(tg). PRL infusion induced cardiac inflammation in CKO;CAkt(tg) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • Fibrosis / metabolism
  • Mice
  • Mice, Transgenic
  • Myocytes, Cardiac / metabolism*
  • Oxidative Stress / physiology
  • Peripartum Period
  • Phosphatidylinositol 3-Kinases / metabolism
  • Pregnancy
  • Proto-Oncogene Proteins c-akt / metabolism*
  • STAT3 Transcription Factor / metabolism*
  • Stress, Physiological / physiology*

Substances

  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt