Shuhei Nishida1, Takeshi Matsumura2, Takafumi Senokuchi1, Saiko Murakami-Nishida1, Norio Ishii1, Yutaro Morita1, Yoshitaka Yagi1, Hiroyuki Motoshima1, Tatsuya Kondo1, Eiichi Araki3. 1. Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan. 2. Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan. Electronic address: takeshim@gpo.kumamoto-u.ac.jp. 3. Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; Center for Metabolic Regulation of Healthy Aging (CMHA), Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Abstract
BACKGROUND AND AIMS: Dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to suppress atherosclerosis progression in atherosclerotic mouse models through unclear mechanisms. In this study, we investigated the effect of the DPP-4 inhibitor, linagliptin, on macrophage polarization in vitro and in vivo. METHODS: Mouse bone marrow macrophages (BMMs) were used in in vitro assays. High fat diet (HFD)-fed Apoe-/- mice were treated orally with linagliptin (10 mg/kg-1•day-1) or a vehicle (water) control. RESULTS: In in vitro assays using BMMs, treatment with LPS and IFNγ decreased the mRNA-expression levels of alternatively activated macrophage (M2) markers, and linagliptin treatment prevented these reductions. The mRNA levels of M2 markers and the number of M2 macrophages in the aorta were higher in linagliptin groups than in control groups. Linagliptin decreased the size of atherosclerotic lesions in HFD-fed Apoe-/- mice. Interestingly, inflammatory stimulation increased DPP-4 expression, and linagliptin suppressed these effects in BMMs. Treatment with DPP-4 small-interfering RNA (siRNA) reproduced linagliptin-mediated alteration of M2 polarization. CONCLUSIONS: Linagliptin increased M2 macrophage polarization by inhibiting DPP-4 expression and activity. These findings may indicate the beneficial effects of DPP-4 inhibitors on the progression of diabetic macrovascular complications.
BACKGROUND AND AIMS: Dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to suppress atherosclerosis progression in atheroscleroticmouse models through unclear mechanisms. In this study, we investigated the effect of the DPP-4 inhibitor, linagliptin, on macrophage polarization in vitro and in vivo. METHODS:Mouse bone marrow macrophages (BMMs) were used in in vitro assays. High fat diet (HFD)-fed Apoe-/- mice were treated orally with linagliptin (10 mg/kg-1•day-1) or a vehicle (water) control. RESULTS: In in vitro assays using BMMs, treatment with LPS and IFNγ decreased the mRNA-expression levels of alternatively activated macrophage (M2) markers, and linagliptin treatment prevented these reductions. The mRNA levels of M2 markers and the number of M2 macrophages in the aorta were higher in linagliptin groups than in control groups. Linagliptin decreased the size of atherosclerotic lesions in HFD-fed Apoe-/- mice. Interestingly, inflammatory stimulation increased DPP-4 expression, and linagliptin suppressed these effects in BMMs. Treatment with DPP-4 small-interfering RNA (siRNA) reproduced linagliptin-mediated alteration of M2 polarization. CONCLUSIONS:Linagliptin increased M2 macrophage polarization by inhibiting DPP-4 expression and activity. These findings may indicate the beneficial effects of DPP-4 inhibitors on the progression of diabetic macrovascular complications.