Anagliptin, a DPP-4 inhibitor, suppresses proliferation of vascular smooth muscles and monocyte inflammatory reaction and attenuates atherosclerosis in male apo e-deficient mice

Nasib Ervinna, Tomoya Mita, Eisuke Yasunari, Kosuke Azuma, Rica Tanaka, Satoshi Fujimura, Dewi Sukmawati, Takashi Nomiyama, Akio Kanazawa, Ryuzo Kawamori, Yoshio Fujitani, Hirotaka Watada

Research output: Contribution to journalArticlepeer-review

138 Citations (Scopus)

Abstract

Dipeptyl peptidase-4 (DPP-4) inhibitors modulate the progression of atherosclerosis. To gain insights into their mechanism of action, 9-wk-old male apolipoprotein E (apoE)-deficient mice were fed a DPP-4 inhibitor, anagliptin-containing diet. The effects of anagliptin were investigated in, a monocyte cell line, human THP-1 cells, and rat smooth muscle cells (SMCs). Treatment with anagliptin for 16wksignificantly reduced accumulation of monocytesandmacrophages in the vascular wall, SMC content in plaque areas, and oil red O-stained area around the aortic valve without affecting glucose tolerance or body weight. Serum DPP-4 concentrations were significantly higher in apoE-deficient mice than control mice, and the levels increased with aging, suggesting the involvement of DPP-4 in the progression of atherosclerosis. Indeed, soluble DPP-4 augmented cultured SMC proliferation, and anagliptin suppressed the proliferation by inhibiting ERK phosphorylation. In THP-1 cells, anagliptin reduced lipopolysaccharide-induced TNFα production with inhibiting ERK phosphorylation and nuclear translocation of nuclear factor-kB. Quantitative analysis also showed that anagliptin reduced the area of atherosclerotic lesion in apoE-deficient mice. These results indicated that the anti-atherosclerotic effect of anagliptin is mediated, at least in part, through its direct inhibition of SMC proliferation and inflammatory reaction of monocytes.

Original languageEnglish
Pages (from-to)1260-1270
Number of pages11
JournalEndocrinology
Volume154
Issue number3
DOIs
Publication statusPublished - 1 Mar 2013

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