Role of reactive oxygen species (ROS) in septic myocardial dysfunction
Acronym: Rosisep
Principal Investigator: Dr. med. Andreas Finkensieper
Team: Heike Fischer, Maria Wartenberg, Saskia Nitza
Research Area: D Sepsis related Organ Failure
Project Number: D1.8
Duration: 01.04.2011 - 31.03.2013
Module: Rotational Position
The Problem
Myocardial dysfunction frequently accompanies severe sepsis and septic shock and is known as septic cardiomyopathy. The management of sepsis-induced myocardial dysfunction remains supportive. Hence it is necessary to increase the knowledge of the pathophysiological as well as the molecular mechanisms which induce septic cardiomyopathy and to develop effcient novel approaches in treatment of septic myocardial dysfunction.
Results so far
The objective of this project is that septic plasma components (cytokines and others) induce an imbalance of reactive oxygen species (ROS) and nitric oxide (NO) in cardiomyocytes and these effects potential control myocardial dysfunction and viability. We postulate that an inhibition of critical members of the NADPH oxidase family may protect cardiomyocytes during sepsis and attenuate the inflammatory process and circumvent septic myocardial dysfunction as well.
Until now our team found a significant up-regulation of the NOX2 enzyme and a parallel down-regulation of the NOS2 enzyme in heart from mice 6 hours post induction of sepsis using the PCI model which was previously standardized by the CSCC. We postulate that these findings could be responsible for an imbalance of ROS and NO. Furthermore, we found an increased amount of Interleukin-1β in serum of septic mice 6 hours post induction of sepsis. In parallel, an up-regulation of transcripts of the Interleukin-1β receptor in the heart of mice derived from septic mice 6 hours post sepsis induction was ascertained. Therefore we propose an Interleukin-1β mediated pathway as one potential way how the expression of NOX2 and NOS2 could be regulated. In parallel, we found an increased ROS generation of beating cluster of cardiomyocytes differentiated from murine ES cells after exposure to serum derived from mice 6 hours post sepsis induction. Furthermore, the analysis of protein obtained from the heart of septic mice 6 hours post sepsis induction showed an increased activity of specific Matrix-Metalloproteases (MMPs). In parallel, an increased mRNA expression of MMP1, 3 and 9 was observed in heart of septic mice.
In conclusion, we postulate an important role of ROS mainly as second messenger during the development of septic myocardial dysfunction in combination with an increased activity of speciἀc MMPs.
Contact
Tel. +49 (0)3641 - 9 32 41 39
Universitätsklinikum Jena
Universitäts-Herzzentrum
Klinik für Innere Medizin I
Erlanger Allee 101
07747 Jena