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）是一种在结构上独特的炎症细胞因子，具有类似趋化因子的活性，是人体先天免疫学和炎症的关键上游介体。它是MIF蛋白家族的创始成员，它涵盖了D-Dopachrome互变异酶（DT）/MIF-2，以及一组跨王国的细菌互变异酶和MIF直系同源物。通过其独特的表达特征，例如在免疫细胞，内皮细胞和心肌细胞中炎症刺激后的半宪法表达和快速释放，MIF的位置是可作为早期炎症和细胞压力传感器的理想位置。由于这种特性及其炎症能力，MIF被发现是急性和慢性炎症和自身免疫性疾病（例如败血性休克和动脉粥样硬化）中的关键介体。尽管MIF在心血管疾病中的活动最初是在动脉粥样硬化的背景下定义的，但在过去的4 - 6年中，我们和其他人的工作已经确定，MIF在心血管疾病中的作用很复杂，并且在对缺血性压力的反应中涉及基本作用。在心脏中，MIF由缺血性心肌细胞，成纤维细胞或内皮细胞释放，并通过自动/旁分泌信号传导起作用。我们小组和其他人的研究确定了MIF作为局部心脏细胞因子具有特异性心脏保护和加剧活动的独特作用。 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.我们自己的翻译发现以及从最近的荟萃分析中获得的数据以及实际专家团队的总体共识，使我们将重点从RIPC问题转移到更深入的机械理解中，对MIF周期性增长的器官保护效果的深入机械理解，并转移到了多大的改善过程中，这是多重的，这是多重的，这是多重的，这与脑部的reperbisition相关，这是经常导致的。与医疗保健相关的成本。