Role of heparanase as a novel therapeutic target in septic cardiomyopathy

败血症心肌病是败血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，并恶化了受影响患者的预后。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，这同时触发内皮细胞糖萼降解产物的释放，如乙酰肝素硫酸盐(损伤相关分子模式)。从机制上讲，感染性心肌病是由于心肌钙(Ca~(2+))调节失调所致。内毒素血症时，由于肌浆网钙-三磷酸腺苷酶(SERCA2)活性的抑制或表达的降低，舒张期的钙再摄取减少。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识别和相互作用仍不清楚。我们认为，乙酰肝素酶是哺乳动物硫酸肝素的主要降解酶，通过释放内源性硫酸肝素片段来调节SERCA2的活性和表达，在败血症心肌病中起重要作用。基于这一假设，我们将研究潜在的治疗干预措施，抑制肝素酶对(I)SERCA2表达/活性，(Ii)感染性心肌病的严重程度，以及(Iii)多菌败血症小鼠存活时间的影响。在阐明了肝素酶和硫酸肝素在败血症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表达和活性所涉及的信号事件。我们认为，阻止SERCA2的表达/活性降低(通过抑制肝素酶)将改善感染性心肌病动物的心功能，进而改善预后。

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.