Role of heparanase as a novel therapeutic target in septic cardiomyopathy

• Applicant: Privatdozent Dr. Lukas Martin
• Subject Area: Anaesthesiology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 407026008

Septic cardiomyopathy is a key feature of the cardiovascular failure associated with sepsis. Its presence complicates the therapeutic management and worsens the prognosis of the affected patient. Septic cardiomyopathy is secondary to an excessive host response to an infection. Thereby, host defence begins with the recognition of pathogens via a set of receptors recognising pathogen-associated molecular patterns, which at the same time triggers the liberation of degradation products of the endothelial glycocalyx, such as heparan sulfates (damage-associated molecular patterns). Mechanistically, septic cardiomyopathy develops as a result of myocardial calcium (Ca2+) dysregulation. The diastolic Ca2+ re-uptake is reduced during endotoxaemia due to the inhibition of either activity or reduced expression of sarcoplasmic reticulum Ca2+-ATP-ase (SERCA2). The identity and interplay of causative factors and signalling pathways responsible for the SERCA2 dysregulation during septic cardiomyopathy, however, remain unknown. We propose that heparanase, the major mammalian heparan sulfates degrading enzyme, regulates the activity and expression of SERCA2 by liberating endogenous heparan sulfate fragments and significantly contributes to septic cardiomyopathy. Based on this hypothesis, we will investigate the effects of potential therapeutic interventions, which inhibit heparanase on (i) SERCA2 expression/activity, (ii) the severity of septic cardiomyopathy, and (iii) survival time of mice subjected to polymicrobial sepsis. Having elucidated the functional role of heparanase and heparan sulfate in septic cardiomyopathy, we will further investigate signalling events involved in heparanase-mediated SERCA2 expression and activity. We assume that preventing the reduction of expression/activity of SERCA2 (by inhibiting heparanase) will improve cardiac function and in turn outcome in animals suffering from septic cardiomyopathy.

• DFG Programme: Research Grants