title: Dipeptidyl peptidase-4 inhibition by gemigliptin prevents abnormal vascular remodeling via NF-E2-related factor 2 activation.
abstract: 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-α-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.
authors.affiliation: Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Seung Hee
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Sungmi
authors.initials: S
authors.lastname: Park
authors.affiliation: Research Institutes of Aging and Metabolism, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Chang Joo
authors.initials: CJ
authors.lastname: Oh
authors.affiliation: Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Jaechan
authors.initials: J
authors.lastname: Leem
authors.affiliation: Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University, Daegu, Republic of Korea; Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
authors.forename: Keun-Gyu
authors.initials: KG
authors.lastname: Park
authors.affiliation: Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University, Daegu, Republic of Korea; Research Institutes of Aging and Metabolism, Kyungpook National University, Daegu, Republic of Korea; Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University, Daegu, Republic of Korea. Electronic address: leei@knu.ac.kr.
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
mesh_terms: D000818:Animals; D020212:Carotid Artery Injuries / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D006965:Hyperplasia; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D058426:Neointima; D010881:Piperidones / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D066253:Vascular Remodeling / Q000187:drug effects*
chemical_list: D015815:Cell Adhesion Molecules; D054873:Dipeptidyl-Peptidase IV Inhibitors; C534891:LC15-0444; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C495637:Nfe2l2 protein, rat; D010881:Piperidones; D011743:Pyrimidines; C000602659:DPP4 protein, rat; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat
keywords: Anti-oxidative stress; Cardiovascular diseases; Carotid artery; Cell cycle; Gemigliptin (PubChem CID: 11953153); Reactive oxygen species; p62–Keap1–Nrf2 pathway