Background: Dipeptidyl peptidase-4 (DPP4) inhibitors suppressed progression of atherosclerosis in atherosclerotic mouse models. However, the role of DPP4 on the progression of atherosclerosis is not clear. We investigated the effect of DPP4 deficiency on the progression of atherosclerosis in DPP4 and apolipoprotein-E double knockout (DPP4/ApoE-DKO) mice.

Methods: Both ApoE-KO mice and DPP4/ApoE-DKO mice were fed with normal chow until 20 weeks of age. Whole aorta and aortic sinus were stained with Oil red O. Bone marrow-derived macrophages (mφ) from wildtype or DPP4-KO mice were used in in vitro study. Expression of iNOS, MCP-1, TNF-α and IL-1β (M1 markers), and arginase-1, Mgl2 and Ym1 (M2 markers) mRNA were evaluated by real-time RT-PCR, and mφ polarization was evaluated by flowcytometry.

Results: There were no differences on food intake, body weight, lipid profiles and the blood glucose levels by insulin tolerance test between each group, but the blood glucose levels by glucose tolerance test were significantly decreased in DPP4/ApoE-DKO mice. Oil-Red-O staining demonstrated that the size of atherosclerotic lesions was significantly smaller in DPP4/ApoE-DKO mice. In in vitro assay, LPS+IFNγ induced the mRNA expression of M1 markers and there was no difference between wildtype mφ and DPP4-KO mφ. On the other hand, the mRNA expression of M2 markers were significantly increased in DPP4-KO mφ. Flowcytometry revealed that the number of iNOS (M1 marker)-positive cells were increased by LPS+IFNγ, which was comparable between wildtype mφ and DPP4-KO mφ. On the other hand, the number of CD206 (M2 marker)-positive cells was higher in DPP4-KO mφ than that in wildtype mφ.

Conclusion: This study suggests that DPP4 deficiency suppresses the progression of atherosclerosis in apoE-KO mice. Moreover, DPP4 deficiency increases the polarization of M2 mφ. These findings may indicate the involvement of DPP4 at least in part on the development of diabetic macrovascular complications.


Y.Zhou: None. T.Matsumura: Research Support; Shimadzu Corporation, Speaker's Bureau; Eli Lilly Japan K.K., Boehringer Ingelheim Japan, Inc. Y.Yagi: None. T.Yoshinaga: None. T.Senokuchi: None. N.Ishii: None. T.Kondo: None. E.Araki: Research Support; Eli Lilly Japan K.K., Nippon Boehringer Ingelheim, Mitsubishi Tanabe Pharma Corporation, Speaker's Bureau; AstraZeneca, Merck & Co., Inc., Ono Pharmaceutical Co., Ltd., Kowa Company, Ltd., Sumitomo Pharma Co., Ltd., Daiichi Sankyo, Novo Nordisk Pharma Ltd.

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