The role of ribonuclease A superfamily as a therapeutic target in septic cardiomyopathy.

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Sepsis is one of the leading causes of death in german intensive care units. According to the definition, it is a systemic inflammatory reaction resulting from an infection. Depending on the severity, it affects the organs. Septic cardiomyopathy is a feared complication of sepsis and will be studied as an example of multi-organ failure in this project. The systemic inflammatory response is induced, among others, by Damage Associated Molecular Patterns (DAMPs) that are released during sepsis. DAMPs are endogenous intracellular molecules that are released from injured or dying cells and cause an inflammatory response. Extracellular RNA (eRNA) belongs to the group of DAMPS and has been shown to have harmful effects on the heart. These deleterious effects of eRNA can be limited by its degradation by naturally occurring ribonuclease (RNases). RNases are components of the innate immune system, belong to the group of endogenous antimicrobial peptides and modulate the local and systemic inflammatory response induced by Pathogen Associated Molecular Patterns (PAMPs) and DAMPs. Human RNase inhibitor 1 (RNH1) is ubiquitously expressed in a variety of tissues and inhibits RNases. In our own preliminary studies we could show that in septic patients RNase 1, 3 and 7 as well as RNH1 are elevated compared to healthy volunteers. In addition, in a murine model of polymicrobial sepsis, we demonstrated that application of RNase 1 reduces cardiac dysfunction and apoptosis in vivo. However, the course of RNases 1, 3, and 7 serum levels and their associations with the clinical course of patients with sepsis and the influence of various DAMPs and PAMPs on their secretion remain unclear. Also unresolved is the role of RNH1 in cardiac dysfunction in vitro and in vivo. The aim of this translational project is to further investigate the role of the RNase A family and its inhibitor RNH1 in septic cardiomyopathy. Serum levels of the proteins will be evaluated in patients with sepsis and the underlying secretion mechanisms will be further analyzed in vitro. The influence of the RNase A family and RNH1 will be further investigated in vivo in a murine polymicrobial sepsis model with respect to their impact on cardiac dysfunction. In the last program point, mechanisms of RNases apart from their nucleolytic function as well as their anti-inflammatory activity in cardiomyocytes will be investigated. In addition, the extent to which RNH1 itself plays an anti-inflammatory role in the PAMPs/DAMPs-induced inflammatory response in cardiomyocytes will be investigated.