title: Carbon monoxide (from CORM-2) inhibits high glucose-induced ICAM-1 expression via AMP-activated protein kinase and PPAR-gamma activations in endothelial cells.
abstract: BACKGROUND
  Hyperglycemia is a risk factor for cardiovascular complications in diabetic state. Hyperglycemia-induced oxidative stress up-regulates intracellular adhesion molecule-1 (ICAM-1) which aggravates endothelial dysfunction, although the underlying mechanisms remain unclear. We hypothesized that carbon monoxide (CO) attenuates ICAM-1 expression induced by high glucose in endothelial cells through activation of AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor gamma (PPAR-gamma) pathway.
  
  
  METHODS
  Human umbilical vein endothelial cells (HUVEC) were pre-treated with CO releasing molecule-2 (CORM-2) alone or in combination with troglitazone or GW1929, PPAR-gamma agonists or GW9662, PPAR-gamma antagonist and then cells were co-treated with high glucose (25mM) for 48h for detection of ICAM-1 expression by Western blot or luciferase assay. The involvement of AMPK on PPAR-gamma and ICAM-1 expressions was tested using pharmacological inducer or inhibitor, as well as transient transfection with AMPK-DN vector.
  
  
  RESULTS
  CO derived from CORM-2 down-regulated ICAM-1 expression induced by high glucose. CORM-2 induced the activity of PPAR-gamma at 24h, and AMPK from 5min to 3h. PPAR-gamma agonists significantly suppressed ICAM-1 expression, whereas in the presence of antagonist (GW9662) CORM-2 failed to inhibit ICAM-1. Thus inhibition of ICAM-1 was dependent on activation of PPAR-gamma. Transfection with AMPK-DN or AMPK inhibitor resulted in attenuation of inducible effect of CORM-2 on PPAR-gamma and subsequently suppressive effect on ICAM-1 expression.
  
  
  CONCLUSIONS
  Our results indicate that PPAR-gamma and AMPK pathways activated by CO are required for attenuation of ICAM-1 expression induced by high glucose. Thus, this study highlights a new property for CO derived from CORM-2 as anti-atherogenic drug for diabetic patients.
authors.affiliation: Department of Pharmarcology, School of Medicine and Institute of Health Sciences, Gyeongsang National University, Biomedical Center (BK21), Jinju, Republic of Korea.
authors.forename: Irina Tsoy
authors.initials: IT
authors.lastname: Nizamutdinova
authors.forename: Young Min
authors.initials: YM
authors.lastname: Kim
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Han Geuk
authors.initials: HG
authors.lastname: Seo
authors.forename: Jae Heun
authors.initials: JH
authors.lastname: Lee
authors.forename: Ki Churl
authors.initials: KC
authors.lastname: Chang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001577:Benzophenones / Q000494:pharmacology; D002248:Carbon Monoxide / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D009942:Organometallic Compounds / Q000378:metabolism / Q000494:pharmacology*; D047495:PPAR gamma / Q000187:drug effects* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012265:Ribonucleotides / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D000077288:Troglitazone; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D000893:Anti-Inflammatory Agents; D001577:Benzophenones; D002839:Chromans; D020536:Enzyme Activators; D007004:Hypoglycemic Agents; D009942:Organometallic Compounds; D047495:PPAR gamma; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D012265:Ribonucleotides; D045162:Thiazolidinediones; C447082:tricarbonyldichlororuthenium (II) dimer; C516138:dorsomorphin; D018799:Intercellular Adhesion Molecule-1; D000620:Aminoimidazole Carboxamide; D014443:Tyrosine; D002248:Carbon Monoxide; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D000077288:Troglitazone; D005947:Glucose; C120099:GW 1929