Role of AKT-glycogen synthase kinase axis in monocyte activation in human beings with and without type 2 diabetes.
Monocyte activation by chemokines is a vital trigger for initiation of atherosclerotic process. Circulating levels of platelet activating factor (PAF), a recognized chemokine, is known to be increased in type 2 diabetes that is linked to accelerated atherosclerosis. To explore the molecular basis we examined the signalling pathways involved in PAF induced monocyte activation. PAF increased migration in monocytes obtained from THP-1 cells, nondiabetic and diabetic subjects. This effect was blocked by AKT inhibition. It did so by phosphorylation of glycogen synthase kinase (GSK)-3betaS(9), which was completely blocked by AKT inhibition. Additionally, PAF induced GSK-3beta phosphorylation was linked to Rac-1 activation and Rho-A inactivation leading to migration. Paradoxically, inhibition of GSK-3beta phosphorylation also augmented monocyte migration in THP-1, ND and diabetic monocytes through phosphorylation of AKT and activation of Rho-A that was independent of GSK. This was validated when (i) overexpression of dominant negative mutants of Rho-A reversed GSK inhibitor induced monocyte migration and (ii) AKT inhibition blocked GSK inhibitor induced Rho-A activity. Constitutively active ARAP3 (Rho-GAP) appears to have a regulatory role in monocyte activity during GSK inhibition. Finally, inhibition of monocyte GSK-3beta activity (by inhibitors and genetic manipulation) led to enhanced migration in diabetes compared to persons without diabetes. We conclude that diabetic monocytes show increased migratory capacity in response to GSK-3beta inhibition. GSK inhibitors developed to treat the metabolic complications of diabetes should therefore be used with caution.
Nandy
Debashis
D
Department of Biochemistry & Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.
Asmann
Yan W
YW
Mukhopadhyay
Debabrata
D
Basu
Ananda
A
D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D055786:Gene Knockout Techniques; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology*; D010972:Platelet Activating Factor / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D010972:Platelet Activating Factor; D047428:Protein Kinase Inhibitors; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3