Role of heparanase as a novel therapeutic target in septic cardiomyopathy

乙酰肝素酶作为脓毒症心肌病新治疗靶点的作用

• 批准号: 407026008
• 负责人: Privatdozent Dr. Lukas Martin
• 金额: --
• 依托单位: Klinik für Operative Intensivmedizin und Intermediate Care
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/407026008?language=en
• 关键词: Role; heparanase; novel; therapeutic; target

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.

脓毒症心肌病是脓毒症相关的心血管衰竭的一个关键特征。它的存在使治疗管理复杂化，并影响患者的预后。脓毒性心肌病是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的降解产物的释放，例如硫酸乙酰肝素（损伤相关分子模式）。从机制上讲，脓毒性心肌病的发展是心肌钙（Ca 2+）失调的结果。内毒素血症期间，由于肌浆网Ca 2 +-ATP酶（SERCA 2）的活性抑制或表达减少，舒张期Ca 2+再摄取减少。然而，脓毒性心肌病期间导致SERCA 2失调的致病因素和信号通路的身份和相互作用仍然未知。我们提出，乙酰肝素酶，主要的哺乳动物硫酸乙酰肝素降解酶，通过释放内源性硫酸乙酰肝素片段调节SERCA 2的活性和表达，并显着有助于脓毒性心肌病。基于这一假设，我们将研究潜在的治疗干预措施的影响，这些干预措施抑制乙酰肝素酶对（i）SERCA 2表达/活性，（ii）脓毒性心肌病的严重程度，和（iii）遭受多微生物脓毒症的小鼠的存活时间。在阐明了乙酰肝素酶和硫酸乙酰肝素在脓毒性心肌病中的功能作用后，我们将进一步研究乙酰肝素酶介导的SERCA 2表达和活性所涉及的信号传导事件。我们假设防止SERCA 2的表达/活性的降低（通过抑制乙酰肝素酶）将改善心脏功能，进而改善患有脓毒性心肌病的动物的结果。