Universität zu Köln

Ricke-Hoch, Melanie, Bultmann, Insa, Stapel, Britta, Condorelli, Gianluigi ORCID: 0000-0003-0481-6843, Rinas, Ursula ORCID: 0000-0003-4940-5749, Sliwa, Karen, Scherr, Michaela and Hilfiker-Kleiner, Denise (2014). Opposing roles of Akt and STAT3 in the protection of the maternal heart from peripartum stress. Cardiovasc. Res., 101 (4). S. 587 - 597. OXFORD: OXFORD UNIV PRESS. ISSN 1755-3245

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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 CKOmice were bred to mice harbouring an Akt transgene, specifically expressed in cardiomyocytes ( CAkt(tg)) generating CKO; CAkt(tg), CAkttg, CKO, and wild-type sibling mice. CAkt(tg) 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; 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 g ( IFN gamma) 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ricke-Hoch, Melanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Bultmann, Insa UNSPECIFIED UNSPECIFIED UNSPECIFIED Stapel, Britta UNSPECIFIED UNSPECIFIED UNSPECIFIED Condorelli, Gianluigi UNSPECIFIED orcid.org/0000-0003-0481-6843 UNSPECIFIED Rinas, Ursula UNSPECIFIED orcid.org/0000-0003-4940-5749 UNSPECIFIED Sliwa, Karen UNSPECIFIED UNSPECIFIED UNSPECIFIED Scherr, Michaela UNSPECIFIED UNSPECIFIED UNSPECIFIED Hilfiker-Kleiner, Denise UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-443335
DOI:	10.1093/cvr/cvu010
Journal or Publication Title:	Cardiovasc. Res.
Volume:	101
Number:	4
Page Range:	S. 587 - 597
Date:	2014
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1755-3245
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SIGNAL TRANSDUCER; CARDIOMYOPATHY; PROLACTIN; FAILURE; TRANSCRIPTION-3; MANAGEMENT; ACTIVATOR; GROWTH; MICE Multiple languages Cardiac & Cardiovascular Systems Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/44333