Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida.
Division of Metabolic and Cardiovascular Sciences, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida.
Transl Res. 2019 Jan;203:1-14. doi: 10.1016/j.trsl.2018.07.006. Epub 2018 Jul 25.
Bone morphogenetic protein-7 (BMP-7) affects the presence of macrophage subtypes in vitro and in vivo at an early stage of atherosclerosis (ATH); however, it remains unknown whether BMP-7 treatment affects the development and progression of ATH at a mid-stage of the disease. We therefore performed a Day 28 (D28) study to examine BMP-7's potential to affect monocyte differentiation. Atherosclerosis was developed in ApoE KO mice, and these animals were treated with intravenous injections of BMP-7 and/or liposomal clodronate (LC). BMP-7 significantly (P < 0.05) lowers plaque formation following induction of atherosclerosis. However, upon macrophage depletion, BMP-7 fails to significantly alter plaque progression suggesting a direct role of BMP-7 on macrophages. Immunohistochemical staining of carotid arteries was performed to determine BMP-7's effect on pro-inflammatory M1 inducible nitric oxide synthase and anti-inflammatory M2 (cluster of differentiation [CD]206, Arginase-1) macrophages, and monocytes ( CD14). BMP-7 significantly reduced pro-inflammatory M1 macrophages and increased anti-inflammatory M2 macrophages at D28, while BMP-7 showed no effect on M2 macrophage differentiation in animals treated with LC. Enzyme-linked immunosorbent assay data showed significant reduction in proinflammatory cytokines (Interleukin-6 [IL-6]), monocyte chemoattractant protein-1, and tumor necrosis factor-α) and a significant increase in anti-inflammatory cytokine (IL-10) in BMP-7 treated mice (P < 0.05).Western blot analysis of arterial tissue confirms a significant increase in pro-survival kinases extracellular-signal regulated kinase and SMAD and a reduction in pro-inflammatory kinases p38 and c-Jun N-terminal kinase in BMP-7 treated mice (P < 0.05). Overall, this study suggests that clodronate treatment inhibits BMP-7 induced differentiation of monocytes into M2 macrophages and improved systolic blood velocity.
骨形态发生蛋白 7（BMP-7）在动脉粥样硬化（ATH）的早期阶段影响体外和体内巨噬细胞亚型的存在；然而，尚不清楚 BMP-7 治疗是否会影响疾病中期 ATH 的发展和进展。因此，我们进行了第 28 天（D28）研究，以检查 BMP-7 影响单核细胞分化的潜力。在 ApoE KO 小鼠中发展动脉粥样硬化，并对这些动物进行静脉注射 BMP-7 和/或脂质体氯膦酸盐（LC）治疗。BMP-7 显著（P < 0.05）降低动脉粥样硬化诱导后的斑块形成。然而，在巨噬细胞耗竭后，BMP-7 未能显著改变斑块进展，表明 BMP-7 对巨噬细胞有直接作用。对颈动脉进行免疫组织化学染色，以确定 BMP-7 对促炎 M1 诱导型一氧化氮合酶和抗炎 M2（分化群[CD]206、精氨酸酶-1）巨噬细胞和单核细胞（CD14）的影响。BMP-7 在 D28 时显著减少促炎 M1 巨噬细胞并增加抗炎 M2 巨噬细胞，而在接受 LC 治疗的动物中，BMP-7 对 M2 巨噬细胞分化没有影响。酶联免疫吸附测定数据显示，BMP-7 治疗的小鼠促炎细胞因子（白细胞介素 6[IL-6]）、单核细胞趋化蛋白 1 和肿瘤坏死因子-α）显著减少，抗炎细胞因子（IL-10）显著增加（P < 0.05）。动脉组织的 Western blot 分析证实，BMP-7 治疗的小鼠中促生存激酶细胞外信号调节激酶和 SMAD 的表达显著增加，促炎激酶 p38 和 c-Jun N-末端激酶的表达显著减少（P < 0.05）。总的来说，这项研究表明氯膦酸盐治疗抑制 BMP-7 诱导单核细胞向 M2 巨噬细胞分化，并改善收缩压血流速度。
