title: Low STAT3 expression sensitizes to toxic effects of β-adrenergic receptor stimulation in peripartum cardiomyopathy.
abstract: 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.
  
  
  
  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 β-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 β1-AR blocker metoprolol or glucose-uptake-promoting drugs perhexiline and etomoxir.
  
  
  
  Iso impairs glucose uptake, induces energy depletion, oxidative stress, dysfunction, and death in STAT3-deficient cardiomyocytes mainly via β1-AR stimulation. These cellular alterations may underlie the dobutamine-induced irreversible heart failure progression in PPCM patients who frequently display reduced cardiac STAT3 expression.
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Stapel
authors.affiliation: Clinic for Internal Medicine III, School of Medicine, Saarland University, 66421 Homburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kohlhaas
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Ricke-Hoch
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany.
authors.forename: Arash
authors.initials: A
authors.lastname: Haghikia
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany.
authors.forename: Sergej
authors.initials: S
authors.lastname: Erschow
authors.affiliation: Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Juhani
authors.initials: J
authors.lastname: Knuuti
authors.affiliation: Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Johanna M U
authors.initials: JM
authors.lastname: Silvola
authors.affiliation: Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Anne
authors.initials: A
authors.lastname: Roivainen
authors.affiliation: Turku PET Centre, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Saraste
authors.affiliation: Clinic for Internal Medicine III, School of Medicine, Saarland University, 66421 Homburg, Germany.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Nickel
authors.affiliation: Clinic for Internal Medicine III, School of Medicine, Saarland University, 66421 Homburg, Germany.
authors.forename: Jasmin A
authors.initials: JA
authors.lastname: Saar
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany.
authors.forename: Irina
authors.initials: I
authors.lastname: Sieve
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pietzsch
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany.
authors.forename: Mirco
authors.initials: M
authors.lastname: Müller
authors.affiliation: Department of Biophysics, CIPMM, School of Medicine, Saarland University, Homburg, Germany.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bogeski
authors.affiliation: Department of Biophysics, CIPMM, School of Medicine, Saarland University, Homburg, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kappl
authors.affiliation: Public Health Genomics Unit, National Institute for Health and Welfare, Genomics and Biomarkers Unit, Helsinki, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Jauhiainen
authors.affiliation: Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: James T
authors.initials: JT
authors.lastname: Thackeray
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Medical School Hannover, Hannover, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Scherr
authors.affiliation: Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Bengel
authors.affiliation: Department of Cardiac Surgery, LMU, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hagl
authors.affiliation: Department of Cardiac, Thoracic, Transplantation and Vascular Surgery, MHH, Hannover, Germany.
authors.forename: Igor
authors.initials: I
authors.lastname: Tudorache
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany.
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
authors.affiliation: Clinic for Internal Medicine III, School of Medicine, Saarland University, 66421 Homburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Maack
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Hilfiker-Kleiner
mesh_terms: D058665:Adrenergic beta-1 Receptor Agonists / Q000009:adverse effects* / Q000633:toxicity*; D000328:Adult; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D009202:Cardiomyopathies / Q000139:chemically induced*; D004280:Dobutamine / Q000009:adverse effects*; D005260:Female; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D018345:Mice, Knockout; D035683:MicroRNAs / Q000502:physiology; D008929:Mitochondria, Heart / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D058725:Peripartum Period; D011644:Puerperal Disorders / Q000188:drug therapy*; D011685:Purine Nucleotides / Q000378:metabolism; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism; D066247:Receptor, ErbB-4 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D001786:Blood Glucose; C549243:MIRN7 microRNA, mouse; D035683:MicroRNAs; C534780:Mirn199 microRNA, mouse; D011685:Purine Nucleotides; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D004280:Dobutamine; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4; D007545:Isoproterenol