Bernadin Ndongson-Dongmo1, Regine Heller1, Dirk Hoyer2, Michael Brodhun3, Michael Bauer4, Johannes Winning5, Emilio Hirsch6, Reinhard Wetzker1, Peter Schlattmann7, Reinhard Bauer8. 1. Institute of Molecular Cell Biology, Jena University Hospital, Friedrich Schiller University, Hans-Knöll-Straße 2, D-07745 Jena, Germany Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany. 2. Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany Biomagnetic Center, Hans Berger Clinic for Neurology, Jena University Hospital, Friedrich Schiller University, Jena, Germany. 3. Department of Pathology, Helios-Klinikum Erfurt, Erfurt, Germany. 4. Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Friedrich Schiller University, Jena, Germany. 5. Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Friedrich Schiller University, Jena, Germany. 6. Molecular Biotechnology Center, University of Torino, Torino, Italy. 7. Institute of Medical Statistics, Computer Sciences and Documentation, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany. 8. Institute of Molecular Cell Biology, Jena University Hospital, Friedrich Schiller University, Hans-Knöll-Straße 2, D-07745 Jena, Germany Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany reinhard.bauer@med.uni-jena.de.
Abstract
AIMS: Sepsis-induced myocardial depression (SIMD), an early and frequent event of infection-induced systemic inflammatory response syndrome (SIRS), is characterized by reduced contractility irrespective of enhanced adrenergic stimulation. Phosphoinositide-3 kinase γ (PI3Kγ) is known to prevent β-adrenergic overstimulation via its scaffold function by activating major cardiac phosphodiesterases and restricting cAMP levels. However, the role of PI3Kγ in SIRS-induced myocardial depression is unknown. This study is aimed at determining the specific role of lipid kinase-dependent and -independent functions of PI3Kγ in the pathogenesis of SIRS-induced myocardial depression. METHODS AND RESULTS: PI3Kγ knockout mice (PI3Kγ(-/-)), mice expressing catalytically inactive PI3Kγ (PI3Kγ(KD/KD)), and wild-type mice (P3Kγ(+/+)) were exposed to lipopolysaccharide (LPS)-induced systemic inflammation and assessed for survival, cardiac autonomic nervous system function, and left ventricular performance. Additionally, primary adult cardiomyocytes were used to analyse PI3Kγ effects on myocardial contractility and inflammatory response. SIRS-induced adrenergic overstimulation induced a transient hypercontractility state in PI3Kγ(-/-) mice, followed by reduced contractility. In contrast, P3Kγ(+/+) mice and PI3Kγ(KD/KD) mice developed an early and ongoing myocardial depression despite exposure to similarly increased catecholamine levels. Compared with cells from P3Kγ(+/+) and PI3Kγ(KD/KD) mice, cardiomyocytes from PI3Kγ(-/-) mice showed an enhanced and prolonged cAMP-mediated signalling upon norepinephrine and an intensified LPS-induced proinflammatory response characterized by nuclear factor of activated T-cells-mediated inducible nitric oxide synthase up-regulation. CONCLUSIONS: This study reveals the lipid kinase-independent scaffold function of PI3Kγ as a mediator of SIMD during inflammation-induced SIRS. Activation of cardiac phosphodiesterases via PI3Kγ is shown to restrict myocardial hypercontractility early after SIRS induction as well as the subsequent inflammatory responses. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Sepsis-induced myocardial depression (SIMD), an early and frequent event of infection-induced systemic inflammatory response syndrome (SIRS), is characterized by reduced contractility irrespective of enhanced adrenergic stimulation. Phosphoinositide-3 kinase γ (PI3Kγ) is known to prevent β-adrenergic overstimulation via its scaffold function by activating major cardiac phosphodiesterases and restricting cAMP levels. However, the role of PI3Kγ in SIRS-induced myocardial depression is unknown. This study is aimed at determining the specific role of lipid kinase-dependent and -independent functions of PI3Kγ in the pathogenesis of SIRS-induced myocardial depression. METHODS AND RESULTS: PI3Kγ knockout mice (PI3Kγ(-/-)), mice expressing catalytically inactive PI3Kγ (PI3Kγ(KD/KD)), and wild-type mice (P3Kγ(+/+)) were exposed to lipopolysaccharide (LPS)-induced systemic inflammation and assessed for survival, cardiac autonomic nervous system function, and left ventricular performance. Additionally, primary adult cardiomyocytes were used to analyse PI3Kγ effects on myocardial contractility and inflammatory response. SIRS-induced adrenergic overstimulation induced a transient hypercontractility state in PI3Kγ(-/-) mice, followed by reduced contractility. In contrast, P3Kγ(+/+) mice and PI3Kγ(KD/KD) mice developed an early and ongoing myocardial depression despite exposure to similarly increased catecholamine levels. Compared with cells from P3Kγ(+/+) and PI3Kγ(KD/KD) mice, cardiomyocytes from PI3Kγ(-/-) mice showed an enhanced and prolonged cAMP-mediated signalling upon norepinephrine and an intensified LPS-induced proinflammatory response characterized by nuclear factor of activated T-cells-mediated inducible nitric oxide synthase up-regulation. CONCLUSIONS: This study reveals the lipid kinase-independent scaffold function of PI3Kγ as a mediator of SIMD during inflammation-induced SIRS. Activation of cardiac phosphodiesterases via PI3Kγ is shown to restrict myocardial hypercontractility early after SIRS induction as well as the subsequent inflammatory responses. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Maria C Silva; Marcela Davoli-Ferreira; Tiago S Medina; Renata Sesti-Costa; Grace K Silva; Carla D Lopes; Lucas E Cardozo; Fábio N Gava; Konstantina Lyroni; Fabrício C Dias; Amanda F Frade; Monique Baron; Helder I Nakaya; Florêncio Figueiredo; José C Alves-Filho; Fernando Q Cunha; Christos Tsatsanis; Christophe Chevillard; Edecio Cunha-Neto; Emilio Hirsch; João S Silva; Thiago M Cunha Journal: Nat Commun Date: 2018-04-17 Impact factor: 14.919