The role of MIF in myocardial ischemic preconditioning

MIF在心肌缺血预适应中的作用

• 批准号: 280719815
• 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
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/280719815?language=en
• 关键词: role; MIF; myocardial; ischemic; preconditioning

Cytokines are well-characterized mediators in the immune response, which are known to be involved in the development and progression of cardiovascular diseases. Macrophage migration inhibitory factor (MIF) belongs to the first cytokines that has been discovered. It is a structurally unique inflammatory cytokine with chemokine-like activities that acts as a key mediator of the innate and acquired immune response. MIF is an upstream regulator of the initial immune response that initiates and exacerbates various chronic and acute inflammatory disorders such as atherosclerosis and sepsis. Detrimental effects of MIF on the heart such as induction of apoptosis in cardiomyocytes and contractile dysfunction in sepsis have been previously observed. In contrast, increasing evidence suggests a time-dependent dual mode of action of MIF during prolonged hypoxia and/or myocardial ischemia/reperfusion (I/R), respectively. In fact, emerging evidence suggests an overall cardioprotective role of MIF within the clinical setting of I/R that becomes in particular relevant for patients with myocardial infarction or for those patients that undergo cardiac surgery. In this context, we already provided first evidence about the significance of perioperative MIF release on the occurrence of organ dysfunctions in cardiac surgical patients with following myocardial I/R. To date, several protective mechanisms and signaling pathways have been identified to provide MIF mediated cardioprotection during ischemia and reperfusion in the heart. Preconditioning has repeatedly been shown to be a powerful strategy to effect myocardial protection against ischemia. This phenomenon establishes a transient protective cellular state in the myocardium by complex and multiple fast-acting signaling steps lasting for few hours. Given the fact that MIF-induced cardioprotective effects are comparable in nature to those that have been identified for ischemic-induced preconditioning and our own preliminary findings that indicated an association between preconditioning-induced MIF release and the activation of the cardioprotective kinases, demonstrate the need for a more comprehensive investigation about the functional role of MIF in preconditioning. Since ischemic preconditioning belongs to the rare promising preservation strategies, which are known to confer cardioprotection, we aim to investigate the functional role of MIF in the underlying pathways. We predict to be able to reveal the potential role of this pleiotropic cytokine in the complex interplay in preconditioning and to discover potential factors, which might influence the extent of MIF secretion in patients exposed to myocardial I/R.

细胞因子是免疫反应中众所周知的介质，已知其参与心血管疾病的发生和进展。巨噬细胞迁移抑制因子（MIF）属于最早被发现的细胞因子。它是一种结构独特的炎症细胞因子，具有趋化因子样活性，是先天性和获得性免疫反应的关键介质。 MIF 是初始免疫反应的上游调节因子，可引发并加剧各种慢性和急性炎症性疾病，如动脉粥样硬化和败血症。先前已观察到 MIF 对心脏的有害影响，例如诱导心肌细胞凋亡和脓毒症中的收缩功能障碍。相反，越来越多的证据表明，MIF 在长时间缺氧和/或心肌缺血/再灌注 (I/R) 期间分别具有时间依赖性双重作用模式。事实上，新出现的证据表明，MIF 在 I/R 临床环境中具有整体心脏保护作用，这对于心肌梗死患者或接受心脏手术的患者尤其重要。在这种情况下，我们已经提供了关于围术期 MIF 释放对伴有心肌缺血再灌注的心脏手术患者器官功能障碍发生的重要性的第一个证据。迄今为止，已确定多种保护机制和信号传导途径可在心脏缺血和再灌注期间提供 MIF 介导的心脏保护作用。预处理已多次被证明是实现心肌缺血保护的有效策略。这种现象通过持续几个小时的复杂且多个快速作用的信号传导步骤在心肌中建立了短暂的保护性细胞状态。鉴于 MIF 诱导的心脏保护作用在本质上与缺血诱导的预处理的效果相当，而且我们自己的初步研究结果表明预处理诱导的 MIF 释放与心脏保护激酶的激活之间存在关联，因此证明有必要更全面地研究 MIF 在预处理中的功能作用。由于缺血预处理属于罕见的有前途的保存策略，已知其具有心脏保护作用，因此我们的目标是研究 MIF 在潜在途径中的功能作用。我们预计能够揭示这种多效性细胞因子在预处理复杂相互作用中的潜在作用，并发现可能影响暴露于心肌缺血再灌注的患者中 MIF 分泌程度的潜在因素。