European heart journal · 2017
Low STAT3 expression sensitizes to toxic effects of β-adrenergic receptor stimulation in peripartum cardiomyopathy.
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Stapel Britta, Kohlhaas Michael, Ricke-Hoch Melanie, Haghikia Arash, Erschow Sergej, Knuuti Juhani, Silvola Johanna M U, Roivainen Anne, Saraste Antti, Nickel Alexander G, Saar Jasmin A, Sieve Irina, Pietzsch Stefan, Müller Mirco, Bogeski Ivan, Kappl Reinhard, Jauhiainen Matti, Thackeray James T, Scherr Michaela, Bengel Frank M, Hagl Christian, Tudorache Igor, Bauersachs Johann, Maack Christoph, Hilfiker-Kleiner Denise
Аннотация
AIMS: 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.
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 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.
CONCLUSIONS: 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.
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 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.
CONCLUSIONS: 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.
Предметные рубрики MeSH
Adrenergic beta-1 Receptor AgonistsAdultAnimalsBlood GlucoseCardiomyopathiesDobutamineFemaleHeart FailureHumansIsoproterenolMaleMice, KnockoutMicroRNAsMitochondria, HeartMyocardiumMyocytes, CardiacPeripartum PeriodPuerperal DisordersPurine NucleotidesRandom AllocationReactive Oxygen SpeciesReceptor, ErbB-4STAT3 Transcription FactorVentricular Dysfunction, Left