Departement de Physiologie (EA 4484), Faculte de Medecine, Universite Lille, IFR 114 (IMPRT), Lille, France.
Crit Care Med. 2013 Jul;41(7):e125-33. doi: 10.1097/CCM.0b013e31827c0d8c.
Macrophage migration inhibitory factor (MIF) has been recognized as a potent proinflammatory mediator that may induce myocardial dysfunction. Mechanisms by which MIF affects cardiac function are not completely elucidated; yet, some macrophage migration inhibitory effects have been related to changes in cytoskeleton architecture. We hypothesized that MIF-induced myocardial dysfunction and mitochondrial respiration deficit could be related to cardiac cell microtubule dynamics alterations.
Prospective, randomized study.
Experimental Cardiovascular Laboratory, University Hospital.
Human myocardial (atrial) trabeculae.
Atrial trabeculae were obtained at the time of cardiac surgery. Isometrically contracting isolated human right atrial trabeculae were exposed to MIF (100 ng/mL) for 60 minutes, in the presence or not of pretreatment with colchicine (10 µM), a microtubule-depolymerizing agent, or paclitaxel (10 µM) a microtubule-stabilizing agent.
Maximal active isometric tension curve and developed isometric force were studied. Trabeculae were then permeabilized for mitochondrial respiration studies using high-resolution oxygraphy. Heart fiber electron microscopy and visualization of βIV tubulin and polymerized actin by confocal microscopy were used to evaluate sarcomere and microtubule disarray. Compared with controls, MIF elicited cardiac contractile and mitochondrial dysfunction, which were largely prevented by pretreatment with colchicine, but not by paclitaxel. Pretreatment with colchicine prevented MIF-induced microtubule network disorganization, excessive tubulin polymerization, and mitochondrial fragmentation. Compound-C, an inhibitor of AMP-activated protein kinase (AMPK), partially prevented contractile dysfunction, suggesting that cardiac deleterious effects of MIF were related to AMPK activation.
MIF depresses human myocardial contractile function and impairs mitochondrial respiration. Changes in microtubule network likely promote MIF-induced cardiac dysfunction by 1) altering with mitochondrial tubular assembly and outer membrane permeability for adenine nucleotides leading to energy deficit, 2) excessive tubulin polymerization that may impede cardiomyocyte viscosity and motion, and 3) interfering with AMPK pathway.
巨噬细胞移动抑制因子（MIF）已被认为是一种强有力的促炎介质，可能导致心肌功能障碍。MIF 影响心脏功能的机制尚未完全阐明；然而，一些巨噬细胞迁移抑制作用与细胞骨架结构的变化有关。我们假设，MIF 诱导的心肌功能障碍和线粒体呼吸缺陷可能与心脏细胞微管动力学的改变有关。
前瞻性、随机研究。
大学医院实验心血管实验室。
人心肌（心房）小梁。
在心脏手术时获得心房小梁。在存在或不存在秋水仙碱（10µM）预处理的情况下，将分离的人心房右小梁进行等长收缩，秋水仙碱是一种微管解聚剂，或紫杉醇（10µM）是一种微管稳定剂，暴露于 MIF（100ng/mL）60 分钟。
研究了最大主动等长张力曲线和发育等长力。然后通过高分辨率耗氧法对小梁进行通透性研究，以研究线粒体呼吸。使用心脏纤维电子显微镜和共聚焦显微镜观察βIV 微管蛋白和聚合肌动蛋白，评估肌节和微管排列紊乱。与对照组相比，MIF 引起心脏收缩和线粒体功能障碍，秋水仙碱预处理可显著预防这些作用，但紫杉醇预处理则不能。秋水仙碱预处理可预防 MIF 诱导的微管网络紊乱、微管蛋白过度聚合和线粒体碎片化。AMP 激活蛋白激酶（AMPK）抑制剂 Compound-C 部分预防了收缩功能障碍，这表明 MIF 的心脏有害作用与 AMPK 激活有关。
MIF 抑制人心肌收缩功能并损害线粒体呼吸。微管网络的变化可能通过以下方式促进 MIF 诱导的心脏功能障碍：1）改变线粒体管状组装和腺嘌呤核苷酸的外膜通透性，导致能量不足；2）过度聚合微管蛋白，可能会阻碍心肌细胞的粘度和运动；3）干扰 AMPK 途径。
