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Phosphoinositide 3-kinase gamma controls inflammation-induced myocardial depression via sequential cAMP and iNOS

Bernadin Ndongson-Dongmo1, Regine Heller1, Dirk Hoyer2

  • 1Institute 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.

Cardiovascular Research
|September 4, 2015
PubMed

Insights

The lipid kinase-independent function of Phosphoinositide-3 kinase γ (PI3Kγ) mediates sepsis-induced myocardial depression (SIMD). PI3Kγ activation of phosphodiesterases restricts early hypercontractility and inflammatory responses during systemic inflammatory response syndrome (SIRS).

Area of Science:

  • Cardiology
  • Molecular Biology
  • Immunology

Background:

  • Sepsis-induced myocardial depression (SIMD) is a common complication of systemic inflammatory response syndrome (SIRS).
  • Phosphoinositide-3 kinase γ (PI3Kγ) is known to regulate $\beta$-adrenergic signaling and cAMP levels in the heart.
  • The specific role of PI3Kγ in SIRS-induced myocardial depression remains unclear.

Purpose of the Study:

  • To determine the role of PI3Kγ's lipid kinase-dependent and -independent functions in the pathogenesis of SIRS-induced myocardial depression.
  • To investigate the mechanisms by which PI3Kγ influences cardiac function during sepsis.

Main Methods:

  • Used PI3Kγ knockout (PI3Kγ(-/-)), catalytically inactive PI3Kγ (PI3Kγ(KD/KD)), and wild-type (PI3Kγ(+/+)) mice exposed to lipopolysaccharide (LPS) for SIRS induction.
  • Assessed survival, cardiac autonomic nervous system function, and left ventricular performance.
  • Analyzed primary adult cardiomyocytes for contractility and inflammatory responses.

Main Results:

  • PI3Kγ(-/-) mice exhibited transient hypercontractility followed by reduced contractility, unlike PI3Kγ(+/+) and PI3Kγ(KD/KD) mice which showed early and sustained myocardial depression.
  • Cardiomyocytes from PI3Kγ(-/-) mice displayed enhanced and prolonged cAMP signaling and intensified pro-inflammatory responses.
  • PI3Kγ activation of phosphodiesterases was shown to restrict myocardial hypercontractility and inflammatory responses.

Conclusions:

  • The lipid kinase-independent scaffold function of PI3Kγ is a key mediator of SIRS-induced myocardial depression.
  • PI3Kγ plays a critical role in regulating cardiac contractility and inflammatory responses during sepsis.
Abstract

Keywords:
Acute inflammationAutonomic nervous systemMyocardial contractilityNFATPhosphoinositide 3-kinase γiNOS

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