title: Blockade of endogenous cytokines mitigates neointimal formation in obese Zucker rats.
abstract: BACKGROUND
  It is well known that diabetes mellitus is a major risk factor for vascular diseases such as atherosclerosis and restenosis after angioplasty. It has become clear that advanced glycation end products (AGE) and their receptor (RAGE) are implicated in vascular diseases, especially in diabetes mellitus. Nevertheless, the mechanisms by which diabetes mellitus is often associated with vascular diseases remain unclear.
  
  
  RESULTS
  To study the role of endogenous cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 in the development of vascular diseases and in the expression of RAGE, we used semapimod, a pharmacological inhibitor of cytokine production, and examined its effect on neointimal formation in the femoral artery of obese Zucker (OZ) rats. We also used an adenovirus construct expressing a dominant negative mutant of the receptor for TNF-alpha (AdTNFRDeltaC) to block the action of endogenous TNF-alpha. Semapimod significantly suppressed neointimal formation and RAGE expression in OZ rats compared with untreated OZ rats. This inhibitory effect of semapimod on neointimal formation was overcome by infection of an adenovirus expressing RAGE into the femoral artery of OZ rats. Furthermore, AdTNFRDeltaC infection significantly suppressed neointimal formation and RAGE expression in the femoral artery of OZ rats.
  
  
  CONCLUSIONS
  These results suggest that endogenous cytokines, especially TNF-alpha, were implicated in neointimal formation in OZ rats and that RAGE was a mediator of the effect of these cytokines on neointimal formation.
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Takeda
authors.forename: Etsu
authors.initials: E
authors.lastname: Suzuki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Satonaka
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Oba
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nishimatsu
authors.forename: Masao
authors.initials: M
authors.lastname: Omata
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Hirata
mesh_terms: D000256:Adenoviridae; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000473:pathology; D003250:Constriction; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000502:physiology; D005263:Femoral Artery / Q000187:drug effects / Q000473:pathology; D005786:Gene Expression Regulation / Q000502:physiology; D005822:Genetic Vectors; D017127:Glycation End Products, Advanced / Q000502:physiology; D006835:Hydrazones / Q000494:pharmacology / Q000627:therapeutic use*; D007333:Insulin Resistance; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D008297:Male; D009765:Obesity / Q000188:drug therapy* / Q000473:pathology; D017434:Protein Structure, Tertiary; D051381:Rats; D011924:Rats, Zucker; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology; D017539:Tunica Intima / Q000473:pathology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D000093242:Interleukin-6 Inhibitors; D000813:Anilides; D006146:Guanidines
chemical_list: D016207:Cytokines; D017127:Glycation End Products, Advanced; D006835:Hydrazones; D007375:Interleukin-1; D015850:Interleukin-6; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D000093242:Interleukin-6 Inhibitors; C097256:semapimod; D000813:Anilides; D006146:Guanidines