Dual role of PI3Kγ in the pathogenesis of septic cardiomyopathy
Acronym: PI3Kgamma
Principal Investigator: Bernadin Ndongson-Dongmo
Scientific Advisors: Prof. Reinhard Bauer, Prof. Reinhard Wetzker
Research Area: D Sepsis related Organ Failure
Project Number: D1.7
Duration: 01.04.2011 - 30.06.2014
Module: PhD Fellowship
The Problem
Cardiac performance during sepsis is impaired due to changes in the macro- and microcirculation, autonomic dysfunction, and inflammation-induced intrinsic myocardial depression. Signaling protein PI3Kγ negatively regulates contractility and relaxation via reduced cAMP availability by phosphodiesterase (PDE) activation preventing β-adrenergic overstimulation but stimulates extracellular remodeling and fibrosis. The project aims to unravel molecular mechanisms of the dual role of PI3Kγ in septic cardiomyopathy and will identify mechanisms for novel approaches in the management and treatment of sepsis-induced myocardial injury.
Results so far
We first searched for an in vivo phenotype in PI3Kγ-deἀcient mice and discovered during early period (3h) of LPS-induced SIRS (10 µg/g) a markedly increased contractility by 71±21%, whereas wildtype mice exhibited reduced myocardial contractility by 26±6% (P<0.05). This was accompanied by disturbed diastolic function in PI3Kγ-deficient mice 24 h after SIRS induction Measurements myocardial function were performed with the pressure-volume conductance catheter technique (MPCU-200™, Millar Instruments, Inc.). We hypothesize that these changes in myocardial function of PI3Kγ-deficient mice represent negative consequences of cardiomyocyte-disturbing muscular over-activation by uncontrolled β-adrenergic overstimulation because of the lack of PI3Kγ-mediated cAMP control in affected cardiomyocytes. Ongoing work aims to unravel if PI3Kγ-mediated β-adrenergic signaling by comparative analysis by PIP3 and/or PDE activation using knockin (PI3Kγ-kinase death) mice.
In addition, primary cell cultures of cardiomyocytes derived from adult mice was established ahead of schedule.
Publications
Schubert H, Eiselt M, Walter B, Fritz H, Brodhun M, Bauer R: Isoflurane/nitrous oxide anesthesia and stress-induced procedures enhance neuroapoptosis in intrauterine growth-restricted piglets. Intensive Care Med 2012, 38:1205-1214.
Richter F, Bauer R, Ebersberger A, Lehmenkuhler A, Schaible HG: Enhanced neuronal excitability in adult rat brainstem causes widespread repetitive brainstem depolarizations with cardiovascular consequences. J Cereb Blood Flow Metab 2012 Mar 28 [Epub ahead of print].
Contact
Tel.: +49 (0)3641 - 9 39 56 36
Universitätsklinikum Jena
Institut für Molekulare Zellbiologie
CMB-Center for Molecular Biomedicine
Hans-Knöll-Straße 2
07745 Jena