Role of heparanase as a novel therapeutic target in septic cardiomyopathy

脓毒性心肌病是脓毒症相关心血管衰竭的一个重要特征。它的存在使治疗管理复杂化，并使患者的预后恶化。感染性心肌病继发于宿主对感染的过度反应。因此，宿主防御开始于通过一组识别病原体相关分子模式的受体识别病原体，这同时触发内皮糖萼降解产物的释放，如硫酸肝素（损伤相关分子模式）。机制上，败血性心肌病的发展是心肌钙（Ca2+）失调的结果。在内毒素血症期间，由于肌浆网Ca2+- atp酶（SERCA2）活性抑制或表达减少，舒张期Ca2+再摄取减少。然而，感染性心肌病中导致SERCA2异常的致病因素和信号通路的身份和相互作用仍然未知。我们认为，哺乳动物硫酸肝素的主要降解酶肝素酶通过释放内源性硫酸肝素片段来调节SERCA2的活性和表达，并在脓毒性心肌病中发挥重要作用。基于这一假设，我们将研究抑制肝素酶对(i) SERCA2表达/活性，（ii）脓毒性心肌病的严重程度，以及（iii）多微生物脓毒症小鼠存活时间的潜在治疗干预的影响。在阐明了肝素酶和硫酸肝素在脓毒性心肌病中的功能作用后，我们将进一步研究肝素酶介导的SERCA2表达和活性的信号事件。我们假设防止SERCA2表达/活性的降低（通过抑制肝素酶）将改善心脏功能，进而改善脓毒性心肌病动物的预后。

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.