The MIF protein family in cardiac ischemia and heart failure: molecular mechanisms and translational avenues

心肌缺血和心力衰竭中的 MIF 蛋白家族：分子机制和转化途径

• 批准号: 443500595
• 负责人: Professor Dr. Jürgen Bernhagen
• 金额: --
• 依托单位: Klinik und Poliklinik für Anästhesiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/443500595?language=en
• 关键词: MIF; protein; family; cardiac; ischemia

Macrophage migration-inhibitory factor (MIF) is a structurally unique, inflammatory cytokine with chemokine-like activities that acts as a key upstream mediator in innate immunity and inflammation in the human body. It is the founding member of the MIF protein family, which encompasses D-dopachrome tautomerase (D-DT)/MIF-2 as well as a group of bacterial tautomerases and MIF orthologs across kingdoms. Through its unique expression characteristics such as semi- constitutive expression and rapid release upon inflammatory stimulation in immune cells, endothelial cells and cardiomyocytes, MIF is ideally positioned to serve as an early inflammatory and cell- stress sensor. Owing to this property and its inflammatory capacity, MIF was found to be a pivotal mediator in acute and chronic inflammatory and autoimmune diseases, such as septic shock and atherosclerosis. Although MIF activities in cardiovascular disease were initially defined in the context of atherosclerosis, work by us and others in the past 4-6 years has now established that MIF’s role in cardiovascular disease is complex and involves a fundamental role in the response to ischemic stress. In the heart, MIF is released by ischemic cardiomyocytes, fibroblasts, or endothelial cells and acts by auto-/paracrine signaling. Studies from our group and others have identified a unique role for MIF as a local cardiac cytokine with phase- specific cardioprotective and exacerbating activities. Our published work in the first funding period demonstrated that while increased MIF levels during myocardial ischemia/reperfusion were associated with a reduced risk for the development of organ dysfunctions, high MIF-2/D- DT levels were predictive of the development of atrial fibrillation and pneumonia, suggesting distinct functions of the MIF homologs in myocardial ischemia/reperfusion injury. Our own translational findings, and data obtained from recent meta-analysis, as well as the overall consensus of actual expert teams, led us to shift our focus from RIPC questions more towards an in-depth mechanistic understanding of the organ-protective effect of the perioperative increase in MIF and towards the following adaptation processes in the heart after myocardial ischemia/reperfusion, which frequently lead to the development of morbidities that are associated with significant healthcare-related costs.

巨噬细胞迁移抑制因子 (MIF) 是一种结构独特的炎症细胞因子，具有趋化因子样活性，是人体先天免疫和炎症的关键上游介质，是 MIF 蛋白家族的创始成员。 D-多巴色素互变异构酶 (D-DT)/MIF-2 以及一组跨界的细菌互变异构酶和 MIF 直系同源物 通过其独特的表达特征。由于免疫细胞、内皮细胞和心肌细胞中炎症刺激时的半组成型表达和快速释放，MIF 非常适合作为早期炎症和细胞应激传感器，由于这种特性及其炎症能力，MIF 被发现可以作为早期炎症和细胞应激传感器。尽管 MIF 在心血管疾病中的活性最初是在动脉粥样硬化的背景下定义的，但它是急性和慢性炎症和自身免疫性疾病的关键介质。等人在过去 4-6 年中已经确定，MIF 在心血管疾病中的作用是复杂的，并且在缺血应激反应中发挥着重要作用。在心脏中，MIF 由缺血的心肌细胞、成纤维细胞或内皮细胞释放并发挥作用。我们小组和其他人的研究已经确定了 MIF 作为局部心脏细胞因子的独特作用，具有特定阶段的心脏保护和加重活性。证明虽然心肌缺血/再灌注期间 MIF 水平升高与器官功能障碍发生风险降低相关，但高 MIF-2/D-DT 水平可预测心房颤动和肺炎的发生，这表明 MIF 的不同功能我们自己的转化研究结果、最近的荟萃分析获得的数据以及实际专家团队的总体共识使我们将注意力从心肌缺血/再灌注损伤中的同系物转移。 RIPC 质疑更多的是对围手术期 MIF 增加的器官保护作用的深入机制理解，以及心肌缺血/再灌注后心脏的以下适应过程，这常常导致与显着相关的发病率的发展。医疗保健相关费用。