The PPAR-gamma activator, Rosiglitazone, inhibits actin polymerisation in monocytes: involvement of Akt and intracellular calcium.
Monocyte hyperactivation as seen in diabetes results in increased cytoskeletal rigidity and reduced cell deformability leading to microchannel occlusions and microvascular complications. The thiazolidinediones (TZDs) are PPAR-gamma agonists that have been reported to exert beneficial non-metabolic effects on the vasculature. This study demonstrates that the TZD, Rosiglitazone, significantly reduces f-MLP-induced actin polymerisation in human monocytic cells (p < 0.05). Two of the key signalling processes known to be involved in the regulation of cytoskeletal remodelling were investigated: PI(3)K-dependent Akt phosphorylation and intracellular calcium concentration [Ca(2+)](i). The PI(3)K inhibitor, Wortmannin, ameliorated f-MLP-induced actin polymerisation (p < 0.05), while the Ca(2+) sequestration inhibitor, thapsigargin, induced actin depolymerisation (p < 0.05), confirming the involvement of both processes in cytoskeletal remodelling. Rosiglitazone significantly reduced f-MLP activation of Akt (p < 0.05), and significantly increased [Ca(2+)](i) in both resting and f-MLP-stimulated cells (p < 0.05). Therefore, Rosiglitazone interacts with signalling events downstream of occupancy of the f-MLP receptor, to modulate cytoskeletal remodelling in a PPAR-gamma-independent manner. To our knowledge, these results are the first to present evidence that a PPAR-gamma agonist can modulate actin remodelling in monocytes, and may therefore be protective against microvascular damage in diabetes.
Singh
Neenu
N
School of Applied Science, University of Wales Institute Cardiff, Western Avenue, Cardiff CF5 2YB, UK.
Webb
Richard
R
Adams
Rachel
R
Evans
Shelley-Ann
SA
Al-Mosawi
Ameena
A
Evans
Marc
M
Roberts
Aled W
AW
Thomas
Andrew W
AW
D000199:Actins / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage*
D000199:Actins; D047495:PPAR gamma; D011518:Proto-Oncogene Proteins; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D009240:N-Formylmethionine Leucyl-Phenylalanine; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium