title: Lipocalin-2 elicited by advanced glycation end-products promotes the migration of vascular smooth muscle cells.
abstract: Advanced glycation end-products (AGEs) play key roles in the development of diabetic vascular complications by activating the proliferation and migration of vascular smooth muscle cells. Here, we identified an increase of the migratory properties of human aortic smooth muscle cells (HASMC) through AGE-induced expression of lipocalin-2 (LCN2). Because the AGE-elicited expression of LCN2 was diminished by an antibody against the AGE receptor (RAGE), diphenylene iodonium (DPI), N-acetyl cysteine, LY294002, and SP600125, we suggest that AGEs enhance the expression of LCN2 via a RAGE-NADPH oxidase-reactive oxygen species pathway, leading to the phosphorylation of PI3K-Akt and JNK in HASMCs. In addition, a chromatin immunoprecipitation assay and promoter assay revealed that CCAAT/enhancer binding protein β is crucial for AGE-induced expression of LCN2. However, any other AGE-related signaling pathway, including ERK1/2, p38, NF-κB, and AP-1, did not affect the AGE- induced expression of LCN2. Knockdown of LCN2 expression by shRNA showed that AGE-elicited LCN2 expression enhanced the invasive and migratory properties of HASMCs, but showed no effect on cell proliferation. Considering the importance of HASMC migration in the development of atherosclerosis, our study provides a novel insight into diabetic vascular complications.
authors.affiliation: Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 626-870, Republic of Korea; Department of Molecular and Cellular Glycobiology, College of Natural Science, Sungkyunkwan University, Suwon, Kyungki-do 440-746, Republic of Korea.
authors.forename: Tae-Wook
authors.initials: TW
authors.lastname: Chung
authors.affiliation: Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 626-870, Republic of Korea.
authors.forename: Hee-Jung
authors.initials: HJ
authors.lastname: Choi
authors.affiliation: Department of Molecular and Cellular Glycobiology, College of Natural Science, Sungkyunkwan University, Suwon, Kyungki-do 440-746, Republic of Korea.
authors.forename: Cheorl-Ho
authors.initials: CH
authors.lastname: Kim
authors.affiliation: Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 626-870, Republic of Korea.
authors.forename: Han-Sol
authors.initials: HS
authors.lastname: Jeong
authors.affiliation: Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 626-870, Republic of Korea. Electronic address: hagis@pusan.ac.kr.
authors.forename: Ki-Tae
authors.initials: KT
authors.lastname: Ha
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D055785:Gene Knockdown Techniques; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D000209:Acute-Phase Proteins; D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; D017127:Glycation End Products, Advanced; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Advanced glycation end-products; Human aortic smooth muscle cells; Invasion; Lipocalin-2; Migration