Rosuvastatin promotes the differentiation of peripheral blood monocytes into M2 macrophages in patients with atherosclerosis by activating PPAR-γ

T. Zhang, B. Shao, G.-A. Liu

Cardiology Center of Suzhou Kowloon Hospital, Shanghai Jiaotong University, Suzhou, China. ximenxiaobaozi@sina.com

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• Pharmacology

OBJECTIVE: 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).

PATIENTS AND METHODS: 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).

RESULTS: 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.

CONCLUSIONS: 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.

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