Carbon monoxide (from CORM-2) inhibits high glucose-induced ICAM-1 expression via AMP-activated protein kinase and PPAR-gamma activations in endothelial cells.
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.
Nizamutdinova
Irina Tsoy
IT
Department of Pharmarcology, School of Medicine and Institute of Health Sciences, Gyeongsang National University, Biomedical Center (BK21), Jinju, Republic of Korea.
Kim
Young Min
YM
Kim
Hye Jung
HJ
Seo
Han Geuk
HG
Lee
Jae Heun
JH
Chang
Ki Churl
KC
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
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