gw-1929 and dorsomorphin

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.. 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.. 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.. 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.

Topics: Aminoimidazole Carboxamide; AMP-Activated Protein Kinases; Anilides; Anti-Inflammatory Agents; Benzophenones; Carbon Monoxide; Cell Adhesion; Cells, Cultured; Chromans; Dose-Response Relationship, Drug; Endothelial Cells; Enzyme Activation; Enzyme Activators; Glucose; Humans; Hypoglycemic Agents; Intercellular Adhesion Molecule-1; Organometallic Compounds; PPAR gamma; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Ribonucleotides; Signal Transduction; Thiazolidinediones; Time Factors; Transfection; Troglitazone; Tyrosine