title: Potential role of HMG CoA reductase inhibitor on oxidative stress induced by advanced glycation endproducts in vascular smooth muscle cells of diabetic vasculopathy.
abstract: Advanced glycation endproducts (AGEs)-induced vascular smooth muscle cell (VSMCs) proliferation and formation of reactive oxygen species (ROS) are emerging as one of the important mechanisms of diabetic vasculopathy but little is known about the antioxidative action of HMG CoA reductase inhibitor (statin) on AGEs. We hypothesized that statin might reduce AGEs-induced intracellular ROS of VSMCs and analyzed the possible mechanism of action of statin in AGEs-induced cellular signaling. Aortic smooth muscle cell of Sprague-Dawley rat (RASMC) culture was done using the different levels of AGEs stimulation in the presence or absence of statin. The proliferation of RASMC, ROS formation and cellular signaling was evaluated and neointimal formation after balloon injury in diabetic rats was analyzed. Increasing concentration of AGEs stimulation was associated with increased RASMC proliferation and increased ROS formation and they were decreased with statin in a dose-dependent manner. Increased NF-kappaB p65, phosphorylated ERK, phosphorylated p38 MAPK, cyclooxygenase-2, and c-jun by AGEs stimulation were noted and their expression was inhibited by statin. Neointimal formation after balloon injury was much thicker in diabetic rats than the sham-treated group but less neointimal growth was observed in those treated with statin after balloon injury. Increased ROS formation, subsequent activation of MAPK system and increased VSMC proliferation may be possible mechanisms of diabetic vasculopathy induced by AGEs and statin may play a key role in the treatment of AGEs-induced diabetic atherosclerosis.
authors.affiliation: Cardiology Division, National Health Insurance Corporation, Ilsan Hospital, Goyang 410-719, Korea.
authors.forename: Se-Jung
authors.initials: SJ
authors.lastname: Yoon
authors.forename: Young Won
authors.initials: YW
authors.lastname: Yoon
authors.forename: Byoung Kwon
authors.initials: BK
authors.lastname: Lee
authors.forename: Hyuck Moon
authors.initials: HM
authors.lastname: Kwon
authors.forename: Ki-Chul
authors.initials: KC
authors.lastname: Hwang
authors.forename: Myunghyun
authors.initials: M
authors.lastname: Kim
authors.forename: Woochul
authors.initials: W
authors.lastname: Chang
authors.forename: Bum-Kee
authors.initials: BK
authors.lastname: Hong
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Lee
authors.forename: Soon-Jung
authors.initials: SJ
authors.lastname: Park
authors.forename: Pil-Ki
authors.initials: PK
authors.lastname: Min
authors.forename: Se-Joong
authors.initials: SJ
authors.lastname: Rim
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D051996:Transcription Factor RelA / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D017127:Glycation End Products, Advanced; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D017382:Reactive Oxygen Species; C498145:Rela protein, rat; D051996:Transcription Factor RelA; D019821:Simvastatin; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D048051:p38 Mitogen-Activated Protein Kinases