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特有的介质，已知参与心血管疾病的发生和发展。巨噬细胞移动抑制因子(MIF)是最早发现的细胞因子。它是一种结构独特的炎性细胞因子，具有趋化因子样的活性，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，启动和加重各种慢性和急性炎症性疾病，如动脉粥样硬化和脓毒症。先前已经观察到MIF对心脏的不利影响，如诱导心肌细胞凋亡和脓毒症时的收缩功能障碍。相反，越来越多的证据表明，在长时间缺氧和/或心肌缺血/再灌注(I/R)期间，MIF分别具有时间依赖性的双重作用模式。事实上，新出现的证据表明，在I/R的临床环境中，MIF具有整体的心脏保护作用，这与心肌梗死患者或接受心脏手术的患者特别相关。在此背景下，我们已经提供了第一个证据，表明围手术期MIF的释放在心脏手术后心肌I/R后器官功能障碍的发生中的重要性。到目前为止，已经确定了几种保护机制和信号通路，在心脏缺血和再灌注期间提供MIF介导的心脏保护。预适应已被反复证明是一种有效的心肌缺血保护策略。这种现象通过持续几个小时的复杂和多个快速反应的信号步骤，在心肌中建立了一种瞬时的保护性细胞状态。鉴于MIF诱导的心脏保护作用在本质上与已发现的缺血诱导预适应相似，以及我们自己的初步发现表明预适应诱导的MIF释放与心脏保护性激酶的激活之间存在关联，表明有必要对MIF在预适应中的功能作用进行更全面的研究。由于缺血预适应属于罕见的有希望的保存策略，已知的授予心脏保护，我们的目标是研究MIF在潜在通路中的功能作用。我们预测能够揭示这种多效性细胞因子在预适应复杂相互作用中的潜在作用，并发现可能影响暴露于心肌I/R患者的MIF分泌程度的潜在因素。