Abstract
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. 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. 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.
Highlights
Sepsis-induced myocardial depression (SIMD) is a frequent event that corresponds to the severity of sepsis and is reversible in survivors.[1]SIMD occurs early in sepsis since a considerable part of septic patients express features of myocardial dysfunction ad admission.[2,3] A reduced myocardial performance may further aggravate the consequences of an already exaggerated systemic host response to infection and B
This study reveals the lipid kinase-independent scaffold function of PI3Kg as a mediator of SIMD during inflammationinduced systemic inflammatory response syndrome (SIRS)
B-adrenergic receptor (b-AR) responsiveness and signalling are attenuated despite enhanced catecholamine availability, which in turn leads to reduced myocardial contractility (MC).[8]
Summary
Sepsis-induced myocardial depression (SIMD) is a frequent event that corresponds to the severity of sepsis and is reversible in survivors.[1]SIMD occurs early in sepsis since a considerable part of septic patients express features of myocardial dysfunction ad admission.[2,3] A reduced myocardial performance may further aggravate the consequences of an already exaggerated systemic host response to infection and B. SIMD occurs early in sepsis since a considerable part of septic patients express features of myocardial dysfunction ad admission.[2,3] A reduced myocardial performance may further aggravate the consequences of an already exaggerated systemic host response to infection and . B-adrenergic receptor (b-AR) responsiveness and signalling are attenuated despite enhanced catecholamine availability, which in turn leads to reduced myocardial contractility (MC).[8] Among a plethora of exogenous and endogenous mediators that may interfere with myocardial function, agonists of the Toll-like receptor 4 (TLR4) are known to activate the phosphatidylinositol 3-kinase (PI3Kg) pathway and to provoke MC depression.[9,10,11]
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