title: Anti-Proliferative Effects of Rutin on OLETF Rat Vascular Smooth Muscle Cells Stimulated by Glucose Variability.
abstract: OBJECTIVE
  Proliferation of vascular smooth muscle cells (VSMCs) plays a crucial role in atherosclerosis. Rutin is a major representative of the flavonol subclass of flavonoids and has various pharmacological activities. Currently, data are lacking regarding its effects on VSMC proliferation induced by intermittent hyperglycemia. Here, we demonstrate the effects of rutin on VSMC proliferation and migration according to fluctuating glucose levels.
  
  
  METHODS
  Primary cultures of male Otsuka Long-Evans Tokushima Fatty (OLETF) rat VSMCs were obtained from enzymatically dissociated rat thoracic aortas. VSMCs were incubated for 72 h with alternating normal (5.5 mmol/L) and high (25.0 mmol/L) glucose media every 12 h. Proliferation and migration of VSMCs, the proliferative molecular pathway [including p44/42 mitogen-activated protein kinases (MAPK), mitogen-activated protein kinase kinase 1/2 (MEK1/2), p38 MAPK, phosphoinositide 3-kinase (PI3K), c-Jun N-terminal protein kinase (JNK), nuclear factor kappa B (NF-κB), and Akt], the migratory pathway (big MAPK 1, BMK1), reactive oxygen species (ROS), and apoptotic pathway were analyzed.
  
  
  RESULTS
  We found enhanced proliferation and migration of VSMCs when cells were incubated in intermittent high glucose conditions, compared to normal glucose. These effects were lowered upon rutin treatment. Intermittent treatment with high glucose for 72 h increased the expression of phospho-p44/42 MAPK (extracellular signal regulated kinase 1/2, ERK1/2), phospho-MEK1/2, phospho-PI3K, phospho-NF-κB, phospho-BMK1, and ROS, compared to treatment with normal glucose. These effects were suppressed by rutin. Phospho-p38 MAPK, phospho-Akt, JNK, and apoptotic pathways [B-cell lymphoma (Bcl)-xL, Bcl-2, phospho-Bad, and caspase-3] were not affected by fluctuations in glucose levels.
  
  
  CONCLUSIONS
  Fluctuating glucose levels increased proliferation and migration of OLETF rat VSMCs via MAPK (ERK1/2), BMK1, PI3K, and NF-κB pathways. These effects were inhibited by the antioxidant rutin.
authors: Division of Endocrinology and Metabolism, Hallym University College of Medicine, Seoul, Korea.
authors: Sung Hoon
authors: SH
authors: Yu
authors: Division of Endocrinology and Metabolism, Hallym University College of Medicine, Seoul, Korea.
authors: Jae Myung
authors: JM
authors: Yu
authors: Division of Endocrinology and Metabolism, Hallym University College of Medicine, Seoul, Korea. hjoonyoo@gmail.com.
authors: Hyung Joon
authors: HJ
authors: Yoo
authors: Division of Endocrinology and Metabolism, Hallym University College of Medicine, Seoul, Korea.
authors: Seong Jin
authors: SJ
authors: Lee
authors: Division of Endocrinology and Metabolism, Hallym University College of Medicine, Seoul, Korea.
authors: Dong Hyun
authors: DH
authors: Kang
authors: Department of Internal Medicine, National Medical Center, Seoul, Korea.
authors: Young Jung
authors: YJ
authors: Cho
authors: Division of Endocrinology and Metabolism, Hallym University College of Medicine, Seoul, Korea.
authors: Doo Man
authors: DM
authors: Kim
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D005419:Flavonoids / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D020334:Rats, Inbred OLETF; D020318:Rats, Long-Evans; D017382:Reactive Oxygen Species / Q000378:metabolism; D012431:Rutin / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D005419:Flavonoids; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D012431:Rutin; D019869:Phosphatidylinositol 3-Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D053148:Caspase 3; D005947:Glucose
keywords: Rutin; hyperglycemia; mitogen-activated protein kinases; phosphatidylinositol 3-kinase; smooth muscle cells