期刊
VASCULAR PHARMACOLOGY
卷 73, 期 -, 页码 11-19出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.vph.2015.07.005
关键词
Anti-oxidative stress; Cardiovascular diseases; Carotid artery; Cell cycle; Reactive oxygen species; p62-Keap1-Nrf2 pathway
资金
- National Research Foundation of Korea (NRF) - Korean Ministry of Education (MOE) [2012R1A2A1A03670452]
- Korea Health Technology R&D Project - Ministry of Health and Welfare, Republic of Korea [HI11C1300]
- Medical Cluster R&D Support Project of Daegu Gyeongbuk Medical Innovation Foundation, Republic of Korea
- National Research Foundation of Korea [2012R1A2A1A03670452] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Dipeptidyl peptidase-4 (DPP-4) inhibitors exert a potent anti-hyperglycemic effect and reduce cardiovascular risk in type 2 diabetic patients. Several studies have shown that DPP-4 inhibitors including sitagliptin have beneficial effects in atherosclerosis and cardiac infarction involving reactive oxygen species. Here, we show that gemigliptin can directly attenuate the abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) via enhanced NF-E2-related factor 2 (Nrf2) activity. Gemigliptin dramatically prevented ligation injury-induced neointimal hyperplasia in mouse carotid arteries. Likewise, the proliferation of primary VSMCs was significantly attenuated by gemigliptin in a dose-dependent manner consistent with a decrease in phospho-Rb, resulting in G1 cell cycle arrest. We found that gemigliptin enhanced Nrf2 activity not only by mRNA expression, but also by increasing Keap1 proteosomal degradation by p62, leading to the induction of Nrf2 target genes such as HO-1 and NQO1. The anti-proliferative role of gemigliptin disappeared with DPP-4 siRNA knockdown, indicating that the endogenous DPP-4 in VSMCs contributed to the effect of gemigliptin. In addition, gemigliptin diminished TNF-alpha-mediated cell adhesion molecules such as MCP-1 and VCAM-1 and reduced MMP2 activity in VSMCs. Taken together, our data indicate that gemigliptin exerts a preventative effect on the proliferation and migration of VSMCs via Nrf2. (C) 2015 Elsevier Inc. All rights reserved.
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