Vanherle Lotte, Matthes Frank, Uhl Franziska E, Meissner Anja
Department of Experimental Medical Science, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden.
Department of Experimental Medical Science, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Department of Physiology, Institute for Theoretical Medicine, University of Augsburg, Augsburg, Germany.
Biomed Pharmacother. 2023 Jun;162:114628. doi: 10.1016/j.biopha.2023.114628. Epub 2023 Apr 3.
Acquired cystic fibrosis transmembrane regulator (CFTR) dysfunctions have been associated with several conditions, including myocardial infarction (MI). Here, CFTR is downregulated in brain, heart, and lung tissue and associates with inflammation and degenerative processes. Therapeutically increasing CFTR expression attenuates these effects. Whether potentiating CFTR function yields similar beneficial effects post-MI is unknown. The CFTR potentiator ivacaftor is currently in clinical trials for treatment of acquired CFTR dysfunction associated with chronic obstructive pulmonary disease and chronic bronchitis. Thus, we tested ivacaftor as therapeutic strategy for MI-associated target tissue inflammation that is characterized by CFTR alterations. MI was induced in male C57Bl/6 mice by ligation of the left anterior descending coronary artery. Mice were treated with ivacaftor starting ten weeks post-MI for two consecutive weeks. Systemic ivacaftor treatment ameliorates hippocampal neuron dendritic atrophy and spine loss and attenuates hippocampus-dependent memory deficits occurring post-MI. Similarly, ivacaftor therapy mitigates MI-associated neuroinflammation (i.e., reduces higher proportions of activated microglia). Systemically, ivacaftor leads to higher frequencies of circulating Ly6C and Ly6C cells compared to vehicle-treated MI mice. Likewise, an ivacaftor-mediated augmentation of MI-associated pro-inflammatory macrophage phenotype characterized by higher CD80-positivity is observed in the MI lung. In vitro, ivacaftor does not alter LPS-induced CD80 and tumor necrosis factor alpha mRNA increases in BV2 microglial cells, while augmenting mRNA levels of these markers in mouse macrophages and differentiated human THP-1-derived macrophages. Our results suggest that ivacaftor promotes contrasting effects depending on target tissue post-MI, which may be largely dependent on its effects on different myeloid cell types.
获得性囊性纤维化跨膜传导调节因子（CFTR）功能障碍与多种疾病相关，包括心肌梗死（MI）。在此，CFTR在脑、心脏和肺组织中表达下调，并与炎症和退行性过程相关。通过治疗性增加CFTR表达可减轻这些影响。MI后增强CFTR功能是否会产生类似的有益效果尚不清楚。CFTR增强剂依伐卡托目前正在进行临床试验，用于治疗与慢性阻塞性肺疾病和慢性支气管炎相关的获得性CFTR功能障碍。因此，我们测试了依伐卡托作为MI相关靶组织炎症的治疗策略，该炎症以CFTR改变为特征。通过结扎左冠状动脉前降支在雄性C57Bl/6小鼠中诱导MI。小鼠在MI后十周开始连续两周接受依伐卡托治疗。全身性依伐卡托治疗可改善海马神经元树突萎缩和棘突丢失，并减轻MI后出现的海马依赖性记忆缺陷。同样，依伐卡托治疗可减轻MI相关的神经炎症（即减少活化小胶质细胞的比例）。在全身，与载体处理的MI小鼠相比，依伐卡托导致循环Ly6C和Ly6C细胞的频率更高。同样，在MI肺中观察到依伐卡托介导的MI相关促炎巨噬细胞表型增强，其特征为CD80阳性率更高。在体外，依伐卡托不会改变脂多糖（LPS）诱导的BV2小胶质细胞中CD80和肿瘤坏死因子α mRNA的增加，而在小鼠巨噬细胞和分化的人THP-1衍生巨噬细胞中增加这些标志物的mRNA水平。我们的结果表明，依伐卡托在MI后根据靶组织促进相反的作用，这可能在很大程度上取决于其对不同髓样细胞类型的作用。
