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

Britta Stapel1, Michael Kohlhaas2, Melanie Ricke-Hoch1

  • 1Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany.

European Heart Journal
|February 16, 2017
PubMed

Insights

Dobutamine may worsen heart failure in peripartum cardiomyopathy (PPCM) patients with low STAT3. STAT3 deficiency impairs cardiac metabolism, leading to heart failure, which can be reversed by blocking beta-1 adrenergic receptors or improving glucose uptake.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Genetics

Background:

  • Peripartum cardiomyopathy (PPCM) is a form of heart failure with controversial treatment options.
  • Reduced cardiac STAT3 expression is observed in PPCM patients.
  • STAT3 deficiency in cardiomyocytes leads to PPCM-like conditions in mice.

Purpose of the Study:

  • To investigate the role of STAT3-dependent signaling in the response to beta-adrenergic receptor (β-AR) agonists in PPCM.
  • To analyze the effects of dobutamine, a β1-AR agonist, on cardiac function in PPCM.

Main Methods:

  • Analysis of STAT3-deficient (CKO) mice and human PPCM patient data.
  • Administration of β-AR agonists (dobutamine, isoproterenol) and blockers (metoprolol) in mouse models.
  • Assessment of cardiac function, metabolism (triglyceride, pyruvate, lactate), and molecular signaling pathways (microRNAs, insulin/glucose transporter-4, neuregulin/ErbB).

Main Results:

  • In severe PPCM patients, dobutamine was associated with heart transplantation or mechanical support, while non-dobutamine treatment improved function.
  • Isoproterenol induced severe heart failure and mortality in STAT3-deficient mice by impairing fatty acid and glucose uptake, causing metabolic deficit.
  • STAT3 deficiency disrupted key signaling pathways, leading to energy depletion, oxidative stress, and cardiomyocyte loss.

Conclusions:

  • Beta-1 adrenergic receptor stimulation impairs glucose uptake and energy metabolism in STAT3-deficient cardiomyocytes, potentially causing irreversible heart failure.
  • These findings suggest that dobutamine may exacerbate heart failure in PPCM patients with reduced STAT3 expression.
  • Metoprolol or glucose-uptake-promoting drugs may offer therapeutic benefits in such cases.
Abstract

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