Cardiology Center of Suzhou Kowloon Hospital, Shanghai Jiaotong University, Suzhou, China.
Eur Rev Med Pharmacol Sci. 2017 Oct;21(19):4464-4471.
To evaluate M2 marker changes in human circulating monocytes before and after rosuvastatin treatment, and to investigate the effects of rosuvastatin on the differentiation of monocytes into M2 macrophages by activating peroxisome proliferator-activated receptor-γ (PPAR-γ).
A total of 20 patients was administrated with rosuvastatin. The human peripheral blood mononuclear cells (PBMCs) were extracted by Ficoll-Hypaque density gradient centrifugation method. PPAR-γ, CD206 and CD163 mRNA levels were detected by Real-time polymerase chain reaction (RT-PCR). The total content of tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), PPAR-γ, extracellular signal-regulated kinase (ERK) and p38 Mitogen-activated protein kinase (MAPK) and the contents of phosphorylated ERK and p38 MAPK were determined by enzyme-linked immunosorbent assay (ELISA).
The expression levels of CD206, Interleukin 10 (IL-10), and chemokine (C-C motif) ligand 18 (CCL18) were significantly improved by rosuvastatin. The expression level of PPAR-γ in circulating monocytes was also distinctly up-regulated through the treatment with rosuvastatin. After rosuvastatin therapy, PPAR-γ mRNA expression was unceasingly increased with time prolonging. The tendency of mRNA level of aP2 was the same as that of PPAR-γ. In vitro experiments indicated that in M2 macrophages, rosuvastatin could enhance the decrease of CD163 expression level induced by interleukin 4 (IL-4). M1 macrophages cultured by supernatant that was used to culture M2 macrophages could significantly inhibit TNF-α and MCP-1 expressions. Rosuvastatin could remarkably induce the phosphorylation of p38 MAPK, but the effect on ERK1/2 was not obvious.
Our results confirmed expressions of M2 markers in human circulating peripheral blood monocytes after rosuvastatin therapy. Both in vivo and in vitro experiments proved that rosuvastatin can induce the expression and activation of PPAR-γ in human monocytes, resulting in the differentiation of monocytes into M2 macrophages.
评估瑞舒伐他汀治疗前后人循环单核细胞中 M2 标志物的变化，并通过激活过氧化物酶体增殖物激活受体-γ（PPAR-γ）研究瑞舒伐他汀对单核细胞分化为 M2 巨噬细胞的影响。
共 20 例患者给予瑞舒伐他汀治疗。采用 Ficoll-Hypaque 密度梯度离心法提取人外周血单个核细胞（PBMC）。通过实时聚合酶链反应（RT-PCR）检测 PPAR-γ、CD206 和 CD163 mRNA 水平。通过酶联免疫吸附试验（ELISA）测定肿瘤坏死因子-α（TNF-α）、单核细胞趋化蛋白-1（MCP-1）、PPAR-γ、细胞外信号调节激酶（ERK）和 p38 丝裂原活化蛋白激酶（MAPK）的总含量以及磷酸化 ERK 和 p38 MAPK 的含量。
瑞舒伐他汀可显著改善 CD206、白细胞介素 10（IL-10）和趋化因子（C-C 基序）配体 18（CCL18）的表达水平。瑞舒伐他汀治疗后，循环单核细胞中 PPAR-γ 的表达也明显上调。瑞舒伐他汀治疗后，PPAR-γ mRNA 表达随时间延长而不断增加。aP2 的 mRNA 水平呈相同趋势。体外实验表明，瑞舒伐他汀可增强白细胞介素 4（IL-4）诱导的 M2 巨噬细胞中 CD163 表达水平的降低。用培养 M2 巨噬细胞的上清液培养的 M1 巨噬细胞可显著抑制 TNF-α和 MCP-1 的表达。瑞舒伐他汀可显著诱导 p38 MAPK 的磷酸化，但对 ERK1/2 的作用不明显。
我们的研究结果证实了瑞舒伐他汀治疗后人循环外周血单核细胞中 M2 标志物的表达。体内和体外实验均证明瑞舒伐他汀可诱导人单核细胞中 PPAR-γ 的表达和激活，导致单核细胞向 M2 巨噬细胞分化。
