Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, China.
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Wuhan 430022, China.
Cardiovasc Res. 2017 Apr 1;113(5):475-487. doi: 10.1093/cvr/cvx027.
Monocytes/macrophages response plays a key role in post-infarction inflammation that contributes greatly to post-infarction ventricular remodelling and cardiac rupture. Therapeutic targeting of the GABAA receptor, which is enriched in monocytes/macrophages but not expressed in the myocardium, may be possible after myocardial infarction (MI).
After MI was induced by ligation of the coronary artery, C57BL/6 mice were intraperitoneally administered with one specific agonist or antagonist of the GABAA receptor (topiramate or bicuculline), in the setting of presence or depletion of monocytes/macrophages. Our data showed that within the first 2 weeks after MI, when monocytes/macrophages dominated, in contrast with bicuculline, topiramate treatment significantly reduced Ly-6Chigh monocyte numbers by regulating splenic monocytopoiesis and promoted foetal derived macrophages preservation and conversion of M1 to M2 or Ly-6Chigh to Ly-6Clow macrophage phenotype in the infarcted heart, though GABAAergic drugs failed to affect M1/M2 or Ly-6Chigh/Ly-6Clow macrophage polarization directly. Accordingly, pro-inflammatory activities mediated by M1 or Ly-6Chigh macrophages were decreased and reparative processes mediated by M2 or Ly-6Clow macrophages were augmented. As a result, post-infarction ventricular remodelling was attenuated, as reflected by reduced infarct size and increased collagen density within infarcts. Echocardiographic indices, mortality and rupture rates were reduced. After depletion of monocytes/macrophages by clodronate liposomes, GABAAergic drugs exhibited no effect on cardiac dysfunction and surrogate clinical outcomes.
Control of the GABAA receptor activity in monocytes/macrophages can potently modulate post-infarction inflammation. Topiramate emerges as a promising drug, which may be feasible to translate for MI therapy in the future.
单核细胞/巨噬细胞反应在梗死后炎症中起关键作用，极大地促进梗死后心室重构和心脏破裂。GABAA 受体在单核细胞/巨噬细胞中丰富，但不在心肌中表达，在心肌梗死后（MI）可能有治疗靶向的可能。
通过结扎冠状动脉诱导 MI 后，在单核细胞/巨噬细胞存在或耗竭的情况下，C57BL/6 小鼠经腹腔给予 GABAA 受体的一种特异性激动剂或拮抗剂（托吡酯或荷包牡丹碱）。我们的数据显示，在 MI 后最初的 2 周内，当单核细胞/巨噬细胞占主导地位时，与荷包牡丹碱相比，托吡酯治疗通过调节脾脏单核细胞生成显著减少 Ly-6Chigh 单核细胞数量，并促进胎儿来源的巨噬细胞的保留以及梗死心脏中 M1 向 M2 或 Ly-6Chigh 向 Ly-6Clow 巨噬细胞表型的转化，尽管 GABAA 能药物未能直接影响 M1/M2 或 Ly-6Chigh/Ly-6Clow 巨噬细胞极化。因此，M1 或 Ly-6Chigh 巨噬细胞介导的促炎活性降低，M2 或 Ly-6Clow 巨噬细胞介导的修复过程增强。结果，梗死后心室重构减弱，表现为梗死面积减小和梗死区内胶原密度增加。超声心动图指标、死亡率和破裂率降低。用氯膦酸盐脂质体耗竭单核细胞/巨噬细胞后，GABAA 能药物对心脏功能障碍和替代临床结局没有影响。
控制单核细胞/巨噬细胞中 GABAA 受体活性可以有效地调节梗死后炎症。托吡酯作为一种有前途的药物出现，未来可能有望转化为 MI 治疗。
