title: The PPAR-gamma activator, Rosiglitazone, inhibits actin polymerisation in monocytes: involvement of Akt and intracellular calcium.
abstract: 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.
authors.affiliation: School of Applied Science, University of Wales Institute Cardiff, Western Avenue, Cardiff CF5 2YB, UK.
authors.forename: Neenu
authors.initials: N
authors.lastname: Singh
authors.forename: Richard
authors.initials: R
authors.lastname: Webb
authors.forename: Rachel
authors.initials: R
authors.lastname: Adams
authors.forename: Shelley-Ann
authors.initials: SA
authors.lastname: Evans
authors.forename: Ameena
authors.initials: A
authors.lastname: Al-Mosawi
authors.forename: Marc
authors.initials: M
authors.lastname: Evans
authors.forename: Aled W
authors.initials: AW
authors.lastname: Roberts
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Thomas
mesh_terms: 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*
chemical_list: 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