Singla Dinender K, Singla Reetu D, Abdelli Latifa S, Glass Carley
Biomolecular Science Center, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, United States of America.
PLoS One. 2015 Mar 13;10(3):e0120739. doi: 10.1371/journal.pone.0120739. eCollection 2015.
Inflammation has been implicated as a perpetrator of diabetes and its associated complications. Monocytes, key mediators of inflammation, differentiate into pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages upon infiltration of damaged tissue. However, the inflammatory cell types, which propagate diabetes progression and consequential adverse disorders, remain unclear. The current study was undertaken to assess monocyte infiltration and the role of fibroblast growth factor-9 (FGF-9) on monocyte to macrophage differentiation and cardioprotection in the diabetic infarcted heart. Db/db diabetic mice were assigned to sham, myocardial infarction (MI), and MI+FGF-9 groups. MI was induced by permanent coronary artery ligation and animals were subjected to 2D transthoracic echocardiography two weeks post-surgery. Immunohistochemical and immunoassay results from heart samples collected suggest significantly increased infiltration of monocytes (Mean ± SEM; MI: 2.02% ± 0.23% vs. Sham 0.75% ± 0.07%; p<0.05) and associated pro-inflammatory cytokines (TNF-α, MCP-1, and IL-6), adverse cardiac remodeling (Mean ± SEM; MI: 33% ± 3.04% vs. Sham 2.2% ± 0.33%; p<0.05), and left ventricular dysfunction (Mean ± SEM; MI: 35.4% ± 1.25% vs. Sham 49.19% ± 1.07%; p<0.05) in the MI group. Importantly, treatment of diabetic infarcted myocardium with FGF-9 resulted in significantly decreased monocyte infiltration (Mean ± SEM; MI+FGF-9: 1.39% ± 0.1% vs. MI: 2.02% ± 0.23%; p<0.05), increased M2 macrophage differentiation (Mean ± SEM; MI+FGF-9: 4.82% ± 0.86% vs. MI: 0.85% ± 0.3%; p<0.05) and associated anti-inflammatory cytokines (IL-10 and IL-1RA), reduced adverse remodeling (Mean ± SEM; MI+FGF-9: 11.59% ± 1.2% vs. MI: 33% ± 3.04%; p<0.05), and improved cardiac function (Fractional shortening, Mean ± SEM; MI+FGF-9: 41.51% ± 1.68% vs. MI: 35.4% ± 1.25%; p<0.05). In conclusion, our data suggest FGF-9 possesses novel therapeutic potential in its ability to mediate monocyte to M2 differentiation and confer cardiac protection in the post-MI diabetic heart.
炎症被认为是糖尿病及其相关并发症的一个促成因素。单核细胞作为炎症的关键介质，在浸润受损组织后会分化为促炎性M1巨噬细胞和抗炎性M2巨噬细胞。然而，促使糖尿病进展及随之而来的不良病症的炎症细胞类型仍不清楚。当前的研究旨在评估单核细胞浸润以及成纤维细胞生长因子9（FGF-9）在糖尿病梗死心脏中对单核细胞向巨噬细胞分化及心脏保护作用的影响。将db/db糖尿病小鼠分为假手术组、心肌梗死（MI）组和MI+FGF-9组。通过永久性冠状动脉结扎诱导心肌梗死，术后两周对动物进行二维经胸超声心动图检查。收集的心脏样本的免疫组织化学和免疫分析结果表明，MI组中单核细胞浸润显著增加（平均值±标准误；MI组：2.02%±0.23%，假手术组：0.75%±0.07%；p<0.05）以及相关促炎细胞因子（TNF-α、MCP-1和IL-6）、不良心脏重塑（平均值±标准误；MI组：33%±3.04%，假手术组：2.2%±0.33%；p<0.05）和左心室功能障碍（平均值±标准误；MI组：35.4%±1.25%，假手术组：49.19%±1.07%；p<0.05）。重要的是，用FGF-9治疗糖尿病梗死心肌导致单核细胞浸润显著减少（平均值±标准误；MI+FGF-9组：1.39%±0.1%，MI组：2.02%±0.23%；p<0.05），M2巨噬细胞分化增加（平均值±标准误；MI+FGF-9组：4.82%±0.86%，MI组：0.85%±0.3%；p<0.05）以及相关抗炎细胞因子（IL-10和IL-1RA），减少不良重塑（平均值±标准误；MI+FGF-9组：11.59%±1.2%，MI组：33%±3.04%；p<0.05），并改善心脏功能（缩短分数，平均值±标准误；MI+FGF-9组：41.51%±1.68%，MI组：35.4%±1.25%；p<0.05）。总之，我们的数据表明FGF-9在介导单核细胞向M2分化以及为心肌梗死后糖尿病心脏提供心脏保护方面具有新的治疗潜力。
