Weipert Kay, Nef Holger, Voss Sandra, Hoffmann Jedrzej, Reischauer Sven, Rolf Andreas, Troidl Kerstin, Wietelmann Astrid, Hamm Christian W, Sossalla Samuel T, Troidl Christian
Department of Internal Medicine I, Division of Cardiology, University Clinic Giessen, Giessen, Germany.
Department of Experimental Cardiology, Kerckhoff Heart and Thorax Center, Bad Nauheim, Germany.
Cardiovasc Ther. 2025 Jun 25;2025:8856808. doi: 10.1155/cdr/8856808. eCollection 2025.
The aim of the present study was to investigate the inhibition of classically activated macrophages in myocardial infarction (MI) under the influence of the chemokine (C-C motif) receptor 2 (CCR2) antagonist propagermanium (PPG). Mice (C57BL/6; = 121) were subjected to occlusion of the left anterior descending artery and were randomized to the following groups: (a) MI with daily oral administration of 0.9% sodium chloride ("MI"), (b) MI with oral administration of 8 mg/kg PPG ("MI + PPG"), and (c) sham-operated mice served as control. Mice were euthanized 2, 5, 10, or 21 days after MI for isolation of total RNA, protein, and immunofluorescence measurements. Flow cytometry was performed to investigate peripheral blood leucocytes. Scar size and cardiac function were determined by MRI on Day 7 after surgery and by trichrome staining on Day 21. PPG administration led to a significantly improved ejection fraction (MI + PPG: 38.5% ± 3.4% vs. MI: 23.8% ± 3.0%; < 0.05) after MI. MRI also revealed improved wall thickness (34.7% ± 3.2% vs. 21.8% ± 2.9%; < 0.05) associated with a diminished akinetic area (13.8% ± 4.0% vs. 37.3% ± 5.6%; < 0.01). Trichrome staining confirmed less collagen scar formation in the PPG-treated group (12.7% ± 1.4% vs. 21.9% ± 3.9%; < 0.05). Flow cytometry showed fewer peripheral blood monocytes in MI + PPG than in MI 2 days after treatment (4.0% ± 0.7% vs. 12.7% ± 1.2% of total leucocytes; < 0.05). Immunostaining and western blotting using activation type-specific markers CCR2 and MRC1 demonstrated that the number of alternatively activated macrophages within the infarct zone increased, whereas the overall number was reduced after PPG treatment. PPG led to increased expression of VEGF- and VEGF- in THP-1 cells in vitro and increased capillary density in vivo 2 days after MI (MI-PPG: 1071 ± 81/mm vs. MI: 648 ± 79/mm ( < 0.05)). Our results suggest that altering the activation type and distribution of invading macrophages in favor of alternative activation improves cardiac remodeling and function following MI.
本研究的目的是探讨趋化因子（C-C基序）受体2（CCR2）拮抗剂普罗瑞林（PPG）对心肌梗死（MI）中经典活化巨噬细胞的抑制作用。将小鼠（C57BL/6；n = 121）进行左前降支动脉闭塞，并随机分为以下几组：（a）心肌梗死组，每日口服0.9%氯化钠（“MI”）；（b）心肌梗死组，口服8 mg/kg PPG（“MI + PPG”）；（c）假手术小鼠作为对照组。在心肌梗死后2、5、10或21天对小鼠实施安乐死，以分离总RNA、蛋白质并进行免疫荧光测量。进行流式细胞术以研究外周血白细胞。在术后第7天通过MRI以及在第21天通过三色染色来测定瘢痕大小和心脏功能。给予PPG后，心肌梗死后射血分数显著改善（MI + PPG：38.5% ± 3.4% vs. MI：23.8% ± 3.0%；P < 0.05）。MRI还显示室壁厚度有所改善（34.7% ± 3.2% vs. 21.8% ± 2.9%；P < 0.05），同时运动不能区域减小（13.8% ± 4.0% vs. 37.3% ± 5.6%；P < 0.01）。三色染色证实PPG治疗组胶原瘢痕形成较少（12.7% ± 1.4% vs. 21.9% ± 3.9%；P < 0.05）。流式细胞术显示治疗后2天MI + PPG组外周血单核细胞比MI组少（占总白细胞的4.0% ± 0.7% vs. 12.7% ± 1.2%；P < 0.05）。使用活化类型特异性标志物CCR2和MRC1进行免疫染色和蛋白质印迹分析表明，梗死区内交替活化巨噬细胞的数量增加，而PPG治疗后巨噬细胞总数减少。PPG导致体外THP-1细胞中VEGF-β和VEGF-δ的表达增加，并在心肌梗死后2天使体内毛细血管密度增加（MI-PPG：1071 ± 81/mm vs. MI：648 ± 79/mm（P < 0.05））。我们的结果表明，改变浸润巨噬细胞的活化类型和分布以利于交替活化可改善心肌梗死后的心脏重塑和功能。
