MIF通过调控SIRT1信号通路减轻心肌缺血再灌注损伤的作用及机制研究

巨噬细胞移动抑制因子（MIF）是一种多效细胞因子，与心肌缺血/再灌注（I/R）损伤密切相关。近年研究发现，心肌中的MIF可通过自分泌/旁分泌方式激活AMPK以及抑制JNK介导的细胞凋亡或者减少氧化应激抗心肌I/R损伤。沉默信息转录调控因子1（SIRT1）是一种NAD+依赖的组蛋白去乙酰化酶，可通过调控能量代谢、抑制凋亡及氧化应激保护心肌I/R损伤。AMPK和SIRT1信号通路是细胞上进化高度保守的能量感受器，它们之间存在正反馈环路。因此，我们提出假说：MIF可以通过调控SIRT1信号通路减少心肌I/R损伤。本课题组以野生型和MIF、CD74基因突变型C57BL/6小鼠为研究对象，观察心肌I/R损伤过程中能量代谢、凋亡以及氧化应激和SIRT1信号通路的变化，并通过使用重组MIF（rMIF）进行干预，诠释MIF/SIRT1信号通路在心肌I/R损伤中的重要作用，为心肌I/R损伤防治提供新思路。

Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that is closely related to myocardial ischemia/reperfusion (I/R) injury. Recent evidence suggest that secreted myocardial MIF acting in an autocrine/paracrine fashion can reduce I/R injury by activating AMPK and suppressing JNK-mediated cell apoptosis. At the same time, MIF provides cardioprotection during I/R by reducing oxidative stress. Silent information regulator 1 (SIRT1) is a type of histone deacetylase whose activity is dependent on nicotinamide adenine dinucleotide (NAD+). The protective of SIRT1 is by regulation energy metabolism, apoptosis and oxidative stress during I/R. The AMPK and SIRT1 signaling pathway are evolutionarily conserved energy sensors in cells. It exert positive feedback loop between AMPK and SIRT1. Hence, we hypothesized that MIF ameliorates I/R injury through modulating the SIRT1 pathway. In the current project, Wild type mice and MIF and CD74 knock-out mice were established I/R model. And observe the change of energy metabolic, apoptosis and oxidative stress during I/R. rMIF was used to further investigate the role of MIF/SIRT1pathway during I/R injury, and provide new insights and targets for the prevention and cure of the myocardial I/R injury.