| First Author | Ndongson-Dongmo B | Year | 2015 |
| Journal | Cardiovasc Res | Volume | 108 |
| Issue | 2 | Pages | 243-53 |
| PubMed ID | 26334033 | Mgi Jnum | J:258892 |
| Mgi Id | MGI:6141961 | Doi | 10.1093/cvr/cvv217 |
| Citation | Ndongson-Dongmo B, et al. (2015) Phosphoinositide 3-kinase gamma controls inflammation-induced myocardial depression via sequential cAMP and iNOS signalling. Cardiovasc Res 108(2):243-53 |
| abstractText | 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 gamma (PI3Kgamma) is known to prevent beta-adrenergic overstimulation via its scaffold function by activating major cardiac phosphodiesterases and restricting cAMP levels. However, the role of PI3Kgamma in SIRS-induced myocardial depression is unknown. This study is aimed at determining the specific role of lipid kinase-dependent and -independent functions of PI3Kgamma in the pathogenesis of SIRS-induced myocardial depression. METHODS AND RESULTS: PI3Kgamma knockout mice (PI3Kgamma(-/-)), mice expressing catalytically inactive PI3Kgamma (PI3Kgamma(KD/KD)), and wild-type mice (P3Kgamma(+/+)) 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 PI3Kgamma effects on myocardial contractility and inflammatory response. SIRS-induced adrenergic overstimulation induced a transient hypercontractility state in PI3Kgamma(-/-) mice, followed by reduced contractility. In contrast, P3Kgamma(+/+) mice and PI3Kgamma(KD/KD) mice developed an early and ongoing myocardial depression despite exposure to similarly increased catecholamine levels. Compared with cells from P3Kgamma(+/+) and PI3Kgamma(KD/KD) mice, cardiomyocytes from PI3Kgamma(-/-) 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 PI3Kgamma as a mediator of SIMD during inflammation-induced SIRS. Activation of cardiac phosphodiesterases via PI3Kgamma is shown to restrict myocardial hypercontractility early after SIRS induction as well as the subsequent inflammatory responses. |
