Dataset Information

Low STAT3 expression sensitizes to toxic effects of ?-adrenergic receptor stimulation in peripartum cardiomyopathy.

ABSTRACT:

Aims

The benefit of the ?1-adrenergic receptor (?1-AR) agonist dobutamine for treatment of acute heart failure in peripartum cardiomyopathy (PPCM) is controversial. Cardiac STAT3 expression is reduced in PPCM patients. Mice carrying a cardiomyocyte-restricted deletion of STAT3 (CKO) develop PPCM. We hypothesized that STAT3-dependent signalling networks may influence the response to ?-AR agonist treatment in PPCM patients and analysed this hypothesis in CKO mice.

Methods and results

Follow-up analyses in 27 patients with severe PPCM (left ventricular ejection fraction ?25%) revealed that 19 of 20 patients not obtaining dobutamine improved cardiac function. All seven patients obtaining dobutamine received heart transplantation (n = 4) or left ventricular assist devices (n = 3). They displayed diminished myocardial triglyceride, pyruvate, and lactate content compared with non-failing controls. The ?-AR agonist isoproterenol (Iso) induced heart failure with high mortality in postpartum female, in non-pregnant female and in male CKO, but not in wild-type mice. Iso induced heart failure and high mortality in CKO mice by impairing fatty acid and glucose uptake, thereby generating a metabolic deficit. The latter was governed by disturbed STAT3-dependent signalling networks, microRNA-199a-5p, microRNA-7a-5p, insulin/glucose transporter-4, and neuregulin/ErbB signalling. The resulting cardiac energy depletion and oxidative stress promoted dysfunction and cardiomyocyte loss inducing irreversible heart failure, which could be attenuated by the ?1-AR blocker metoprolol or glucose-uptake-promoting drugs perhexiline and etomoxir.

Conclusions

Iso impairs glucose uptake, induces energy depletion, oxidative stress, dysfunction, and death in STAT3-deficient cardiomyocytes mainly via ?1-AR stimulation. These cellular alterations may underlie the dobutamine-induced irreversible heart failure progression in PPCM patients who frequently display reduced cardiac STAT3 expression.

SUBMITTER: Stapel B

PROVIDER: S-EPMC5381590 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Publications

Low STAT3 expression sensitizes to toxic effects of β-adrenergic receptor stimulation in peripartum cardiomyopathy.

Stapel Britta B Kohlhaas Michael M Ricke-Hoch Melanie M Haghikia Arash A Erschow Sergej S Knuuti Juhani J Silvola Johanna M U JM Roivainen Anne A Saraste Antti A Nickel Alexander G AG Saar Jasmin A JA Sieve Irina I Pietzsch Stefan S Müller Mirco M Bogeski Ivan I Kappl Reinhard R Jauhiainen Matti M Thackeray James T JT Scherr Michaela M Bengel Frank M FM Hagl Christian C Tudorache Igor I Bauersachs Johann J Maack Christoph C Hilfiker-Kleiner Denise D

European heart journal 20170201 5

<h4>Aims</h4>The benefit of the β1-adrenergic receptor (β1-AR) agonist dobutamine for treatment of acute heart failure in peripartum cardiomyopathy (PPCM) is controversial. Cardiac STAT3 expression is reduced in PPCM patients. Mice carrying a cardiomyocyte-restricted deletion of STAT3 (CKO) develop PPCM. We hypothesized that STAT3-dependent signalling networks may influence the response to β-AR agonist treatment in PPCM patients and analysed this hypothesis in CKO mice.<h4>Methods and results</h ...[more]

PMID: 28201733

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