title: Insulin regulates monocyte trans-endothelial migration through surface expression of macrophage-1 antigen.
abstract: During the pathogenesis of atherosclerosis, adhesion of monocytes to vascular endothelium and subsequent migration across the endothelium has been recognized as a key process in the chronic inflammatory response in atherosclerosis. As type 2 diabetes is closely associated with the pathogenesis of atherosclerosis, we investigated whether monocyte adhesion and migration were affected by insulin. We found that insulin activated Akt and induced subsequent migration in THP-1. However, glucose and insulin-like growth factor-1, which is a growth factor that is structurally similar to insulin, were not effective. Insulin-dependent migration of THP-1 was blocked by inhibition of PI3K or Akt and by silencing of Akt1. Insulin-dependent migration of bone marrow-derived monocytic cells (BDMCs) was attenuated by inhibition of PI3K and Akt. In addition, BDMCs from Akt1(-/-) mice showed defects in insulin-dependent migration. Stimulation of THP-1 with insulin caused adhesion with human vein endothelial cells (HUVECs) that was blocked by silencing of Akt1. However, stimulation of HUVECs did not cause adhesion with THP-1. Moreover, BDMCs from Akt1(-/-) mice showed defects in insulin-dependent adhesion with HUVECs. Insulin induced surface expression of Mac-1, and neutralization of Mac-1 blocked insulin-induced adhesion of THP-1 as well as BDMCs. Surface expression of Mac-1 was blocked in THP-1 with silenced Akt1, and in BDMCs isolated from mice lacking Akt1. Finally, trans-endothelial migration of THP-1 and BDMCs was blocked by Mac-1-neutralizing antibody, in THP-1 with silenced Akt1 and in BDMCs from Akt1(-/-) mice. These results suggest that insulin stimulates monocyte trans-endothelial migration through Akt-dependent surface expression of Mac-1, which may be part of the atherogenesis in type 2 diabetes.
authors.affiliation: MRC for Ischemic Tissue Regeneration, Medical Research Institute, and Department of Pharmacology, Pusan National University School of Medicine, Yangsan, Republic of Korea.
authors.forename: Seo Yeon
authors.initials: SY
authors.lastname: Jin
authors.affiliation: MRC for Ischemic Tissue Regeneration, Medical Research Institute, and Department of Pharmacology, Pusan National University School of Medicine, Yangsan, Republic of Korea.
authors.forename: Eun Kyoung
authors.initials: EK
authors.lastname: Kim
authors.affiliation: MRC for Ischemic Tissue Regeneration, Medical Research Institute, and Department of Pharmacology, Pusan National University School of Medicine, Yangsan, Republic of Korea.
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Ha
authors.affiliation: Department of Obstetrics and Gynecology, Pusan National University School of Medicine, Yangsan, Republic of Korea.
authors.forename: Dong Hyung
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Cardiovascular Disease Center, Pusan National University Hospital, Pusan National University School of Medicine, Yangsan, Republic of Korea.
authors.forename: Jeong Su
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Pusan National University Hospital, Pusan National University School of Medicine, Yangsan, Republic of Korea.
authors.forename: Il Young
authors.initials: IY
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Pusan National University Hospital, Pusan National University School of Medicine, Yangsan, Republic of Korea.
authors.forename: Sang Heon
authors.initials: SH
authors.lastname: Song
authors.affiliation: Department of Anatomy, Pusan National University School of Korean Medicine, Yangsan, Republic of Korea.
authors.forename: Hwa Kyoung
authors.initials: HK
authors.lastname: Shin
authors.affiliation: MRC for Ischemic Tissue Regeneration, Medical Research Institute, and Department of Pharmacology, Pusan National University School of Medicine, Yangsan, Republic of Korea.
authors.forename: Chi Dae
authors.initials: CD
authors.lastname: Kim
authors.affiliation: MRC for Ischemic Tissue Regeneration, Medical Research Institute, and Department of Pharmacology, Pusan National University School of Medicine, Yangsan, Republic of Korea. Electronic address: sunsik@pusan.ac.kr.
authors.forename: Sun Sik
authors.initials: SS
authors.lastname: Bae
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D007328:Insulin; D016177:Macrophage-1 Antigen; D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
keywords: Adhesion; Akt; Migration; Monocyte infiltration; PI3K